Inhibitors of Bruton&#39;s Tyrosine Kinase

ABSTRACT

This application discloses 6-(2-Hydroxymethyl-phenyl)-2-methyl-2H-pyridazin-3-one derivatives according to generic Formula I: 
     
       
         
         
             
             
         
       
     
     wherein, variables X, R, and Y 4 , are defined as described herein, which inhibit Btk. The compounds disclosed herein are useful to modulate the activity of Btk and treat diseases associated with excessive Btk activity. The compounds are further useful to treat inflammatory and auto immune diseases associated with aberrant B-cell proliferation, such as rheumatoid arthritis. Also disclosed are compositions containing compounds of Formula I and at least one carrier, diluent or excipient.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is entitled to the benefit of U.S. provisional patentapplication Ser. No. 61/372,887 filed on Aug. 12, 2010 and U.S.provisional patent application Ser. No. 61/497,093 filed on Jun. 15,2011, the disclosures of which are incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to the use of novel derivatives whichinhibit Btk and are useful for the treatment of auto-immune andinflammatory diseases caused by aberrant B-cell activation. The novel6-(2-Hydroxymethyl-phenyl)-2-methyl-2H-pyridazin-3-one derivativesdescribed herein are useful for the treatment of arthritis.

Protein kinases constitute one of the largest families of human enzymesand regulate many different signaling processes by adding phosphategroups to proteins (T. Hunter, Cell 1987 50:823-829). Specifically,tyrosine kinases phosphorylate proteins on the phenolic moiety oftyrosine residues. The tyrosine kinase family includes members thatcontrol cell growth, migration, and differentiation. Abnormal kinaseactivity has been implicated in a variety of human diseases includingcancers, autoimmune and inflammatory diseases. Since protein kinases areamong the key regulators of cell signaling they provide a target tomodulate cellular function with small molecular kinase inhibitors andthus make good drug design targets. In addition to treatment ofkinase-mediated disease processes, selective and efficacious inhibitorsof kinase activity are also useful for investigation of cell signalingprocesses and identification of other cellular targets of therapeuticinterest.

There is good evidence that B-cells play a key role in the pathogenesisof autoimmune and/or inflammatory disease. Protein-based therapeuticsthat deplete B cells such as Rituxan are effective againstautoantibody-driven inflammatory diseases such as rheumatoid arthritis(Rastetter et al. Annu Rev Med 2004 55:477). Therefore inhibitors of theprotein kinases that play a role in B-cell activation should be usefultherapeutics for B-cell mediated disease pathology such as autoantibodyproduction.

Signaling through the B-cell receptor (BCR) controls a range of B-cellresponses including proliferation and differentiation into matureantibody producing cells. The BCR is a key regulatory point for B-cellactivity and aberrant signaling can cause deregulated B-cellproliferation and formation of pathogenic autoantibodies that lead tomultiple autoimmune and/or inflammatory diseases. Bruton's TyrosineKinase (Btk) is a non-BCR associated kinase that is membrane proximaland immediately downstream from BCR. Lack of Btk has been shown to blockBCR signaling and therefore inhibition of Btk could be a usefultherapeutic approach to block B-cell mediated disease processes.

Btk is a member of the Tec family of tyrosine kinases, and has beenshown to be a critical regulator of early B-cell development and matureB-cell activation and survival (Khan et al. Immunity 1995 3:283;Ellmeier et al. J. Exp. Med. 2000 192:1611). Mutation of Btk in humansleads to the condition X-linked agammaglobulinemia (XLA) (reviewed inRosen et al. New Eng. J. Med. 1995 333:431 and Lindvall et al. Immunol.Rev. 2005 203:200). These patients are immunocompromised and showimpaired maturation of B-cells, decreased immunoglobulin and peripheralB-cell levels, diminished T-cell independent immune responses as well asattenuated calcium mobilization following BCR stimulation.

Evidence for a role for Btk in autoimmune and inflammatory diseases hasalso been provided by Btk-deficient mouse models. In preclinical murinemodels of systemic lupus erythematosus (SLE), Btk-deficient mice showmarked amelioration of disease progression. In addition, Btk-deficientmice are resistant to collagen-induced arthritis (Jansson and HolmdahlClin. Exp. Immunol. 1993 94:459). A selective Btk inhibitor has beendemonstrated dose-dependent efficacy in a mouse arthritis model (Z. Panet al., Chem. Med. Chem. 2007 2:58-61).

Btk is also expressed by cells other than B-cells that may be involvedin disease processes. For example, Btk is expressed by mast cells andBtk-deficient bone marrow derived mast cells demonstrate impairedantigen induced degranulation (Iwaki et al. J. Biol. Chem. 2005280:40261). This shows Btk could be useful to treat pathological mastcells responses such as allergy and asthma. Also monocytes from XLApatients, in which Btk activity is absent, show decreased TNF alphaproduction following stimulation (Horwood et al. J Exp Med 197:1603,2003). Therefore TNF alpha mediated inflammation could be modulated bysmall molecular Btk inhibitors. Also, Btk has been reported to play arole in apoptosis (Islam and Smith Immunol. Rev. 2000 178:49,) and thusBtk inhibitors would be useful for the treatment of certain B-celllymphomas and leukemias (Feldhahn et al. J. Exp. Med. 2005 201:1837,).

SUMMARY OF THE INVENTION

The present application provides the Btk inhibitor compounds of FormulaI, methods of use thereof, as described herein below:

The application provides a compound of Formula I,

wherein:

is either a single or double bond;X is either CH, CH₂, or N;

R is H, -R¹, -R¹-R²-R³, -R¹-R³, or -R²-R³;

R¹ is aryl, heteroaryl, bicyclic heteroaryl, cycloalkyl, orheterocycloalkyl, each of which is optionally substituted with one ormore lower alkyl, hydroxy, hydroxy lower alkyl, lower alkoxy, halo,nitro, amino, amido, cyano, oxo, or lower haloalkyl;

R² is —C(═O), —C(═O)O, —C(═O)NR^(2′), —NHC(═O)O, —C(R^(2′))₂, —O, —S,—C(═NH)NR^(2′), or —S(═O)₂;

each R^(2′) is independently H or lower alkyl;

R³ is H or R⁴;

R⁴ is lower alkyl, lower haloalkyl, lower alkoxy, amino, lower alkylamino, cycloalkyl amino, lower dialkyl amino, aryl, arylalkyl,alkylaryl, heteroaryl, alkyl heteroaryl, heteroaryl alkyl, cycloalkyl,alkyl cycloalkyl, cycloalkyl alkyl, heterocycloalkyl, alkylheterocycloalkyl, heterocycloalkyl alkyl, bicyclic cycloalkyl, bicyclicheterocycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, or bicyclicspiroheterocycloalkyl, each of which is optionally substituted with oneor more lower alkyl, halo, lower alkyl amino, lower dialkyl amino,hydroxy, hydroxy lower alkyl, lower alkoxy, lower alkanoyl, halo, nitro,amino, amido, acyl, cyano, oxo, sulfonyl, lower alkyl sulfonyl,guanidino, hydroxyl amino, carboxy, carbamoyl, carbamate, halo loweralkoxy, heterocycloalkyl, or halo lower alkyl, wherein two lower alkylgroups may together form a ring;

Y⁴ is Y^(4a), Y^(4b), Y^(4c), or Y^(4d);

Y^(4a) is H or halogen;

Y^(4b) is lower alkyl, optionally substituted with one or moresubstituents selected from the group consisting of lower haloalkyl,halogen, hydroxy, amino, cyano, and lower alkoxy;

Y^(4c) is lower cycloalkyl, optionally substituted with one or moresubstituents selected from the group consisting of lower alkyl, lowerhaloalkyl, halogen, hydroxy, amino, cyano, and lower alkoxy; and

Y^(4d) is amino, optionally substituted with one or more lower alkyl,alkoxy lower alkyl, or hydroxy lower alkyl;

or a pharmaceutically acceptable salt thereof.

The application provides a method for treating an inflammatory and/orautoimmune condition comprising administering to a patient in needthereof a therapeutically effective amount of the Btk inhibitor compoundof Formula I.

The application provides a pharmaceutical composition comprising the Btkinhibitor compound of any one of Formula I, admixed with at least onepharmaceutically acceptable carrier, excipient or diluent.

DETAILED DESCRIPTION OF THE INVENTION Definitions

The phrase “a” or “an” entity as used herein refers to one or more ofthat entity; for example, a compound refers to one or more compounds orat least one compound. As such, the terms “a” (or “an”), “one or more”,and “at least one” can be used interchangeably herein.

The phrase “as defined herein above” refers to the broadest definitionfor each group as provided in the Summary of the Invention or thebroadest claim. In all other embodiments provided below, substituentswhich can be present in each embodiment and which are not explicitlydefined retain the broadest definition provided in the Summary of theInvention.

As used in this specification, whether in a transitional phrase or inthe body of the claim, the terms “comprise(s)” and “comprising” are tobe interpreted as having an open-ended meaning. That is, the terms areto be interpreted synonymously with the phrases “having at least” or“including at least”. When used in the context of a process, the term“comprising” means that the process includes at least the recited steps,but may include additional steps. When used in the context of a compoundor composition, the term “comprising” means that the compound orcomposition includes at least the recited features or components, butmay also include additional features or components.

As used herein, unless specifically indicated otherwise, the word “or”is used in the “inclusive” sense of “and/or” and not the “exclusive”sense of “either/or”.

The term “independently” is used herein to indicate that a variable isapplied in any one instance without regard to the presence or absence ofa variable having that same or a different definition within the samecompound. Thus, in a compound in which R″ appears twice and is definedas “independently carbon or nitrogen”, both R″s can be carbon, both R″scan be nitrogen, or one R″ can be carbon and the other nitrogen.

When any variable occurs more than one time in any moiety or formuladepicting and describing compounds employed or claimed in the presentinvention, its definition on each occurrence is independent of itsdefinition at every other occurrence. Also, combinations of substituentsand/or variables are permissible only if such compounds result in stablecompounds.

The symbols “*” at the end of a bond or “

” drawn through a bond each refer to the point of attachment of afunctional group or other chemical moiety to the rest of the molecule ofwhich it is a part. Thus, for example:

MeC(═O)OR⁴ wherein

A bond drawn into ring system (as opposed to connected at a distinctvertex) indicates that the bond may be attached to any of the suitablering atoms.

The term “optional” or “optionally” as used herein means that asubsequently described event or circumstance may, but need not, occur,and that the description includes instances where the event orcircumstance occurs and instances in which it does not. For example,“optionally substituted” means that the optionally substituted moietymay incorporate a hydrogen atom or a substituent.

The phrase “optional bond” means that the bond may or may not bepresent, and that the description includes single, double, or triplebonds. If a substituent is designated to be a “bond” or “absent”, theatoms linked to the substituents are then directly connected.

The term “about” is used herein to mean approximately, in the region of,roughly, or around. When the term “about” is used in conjunction with anumerical range, it modifies that range by extending the boundariesabove and below the numerical values set forth. In general, the term“about” is used herein to modify a numerical value above and below thestated value by a variance of 20%.

Certain compounds of Formula I may exhibit tautomerism. Tautomericcompounds can exist as two or more interconvertable species. Prototropictautomers result from the migration of a covalently bonded hydrogen atombetween two atoms. Tautomers generally exist in equilibrium and attemptsto isolate an individual tautomers usually produce a mixture whosechemical and physical properties are consistent with a mixture ofcompounds. The position of the equilibrium is dependent on chemicalfeatures within the molecule. For example, in many aliphatic aldehydesand ketones, such as acetaldehyde, the keto form predominates while; inphenols, the enol form predominates. Common prototropic tautomersinclude keto/enol (—C(═O)—CH—{right arrow over (→)}—C(—OH)═CH—),amide/imidic acid (—C(═O)—NH—{right arrow over (→)}—C(—OH)═N—) andamidine (—C(═NR)—NH—{right arrow over (→)}—C(—NHR)═N—) tautomers. Thelatter two are particularly common in heteroaryl and heterocyclic ringsand the present invention encompasses all tautomeric forms of thecompounds.

Technical and scientific terms used herein have the meaning commonlyunderstood by one of skill in the art to which the present inventionpertains, unless otherwise defined. Reference is made herein to variousmethodologies and materials known to those of skill in the art. Standardreference works setting forth the general principles of pharmacologyinclude Goodman and Gilman's The Pharmacological Basis of Therapeutics,10^(th) Ed., McGraw Hill Companies Inc., New York (2001). Any suitablematerials and/or methods known to those of skill can be utilized incarrying out the present invention. However, preferred materials andmethods are described. Materials, reagents and the like to whichreference are made in the following description and examples areobtainable from commercial sources, unless otherwise noted.

The definitions described herein may be appended to formchemically-relevant combinations, such as “heteroalkylaryl,”“haloalkylheteroaryl,” “arylalkylheterocyclyl,” “alkylcarbonyl,”“alkoxyalkyl,” and the like. When the term “alkyl” is used as a suffixfollowing another term, as in “phenylalkyl,” or “hydroxyalkyl,” this isintended to refer to an alkyl group, as defined above, being substitutedwith one to two substituents selected from the other specifically-namedgroup. Thus, for example, “phenylalkyl” refers to an alkyl group havingone to two phenyl substituents, and thus includes benzyl, phenylethyl,and biphenyl. An “alkylaminoalkyl” is an alkyl group having one to twoalkylamino substituents. “Hydroxyalkyl” includes 2-hydroxyethyl,2-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl,2,3-dihydroxybutyl, 2-(hydroxymethyl), 3-hydroxypropyl, and so forth.Accordingly, as used herein, the term “hydroxyalkyl” is used to define asubset of heteroalkyl groups defined below. The term -(ar)alkyl refersto either an unsubstituted alkyl or an aralkyl group. The term(hetero)aryl or (het)aryl refers to either an aryl or a heteroarylgroup.

The term “spirocycloalkyl”, as used herein, means a spirocycliccycloalkyl group, such as, for example, spiro[3.3]heptane. The termspiroheterocycloalkyl, as used herein, means a spirocyclicheterocycloalkyl, such as, for example, 2,6-diaza spiro[3.3]heptane.

The term “acyl” as used herein denotes a group of formula —C(═O)Rwherein R is hydrogen or lower alkyl as defined herein. The term or“alkylcarbonyl” as used herein denotes a group of formula C(═O)R whereinR is alkyl as defined herein. The term C₁₋₆ acyl refers to a group—C(═O)R contain 6 carbon atoms. The term “arylcarbonyl” as used hereinmeans a group of formula C(═O)R wherein R is an aryl group; the term“benzoyl” as used herein an “arylcarbonyl” group wherein R is phenyl.

The term “ester” as used herein denotes a group of formula —C(═O)ORwherein R is lower alkyl as defined herein.

The term “alkyl” as used herein denotes an unbranched or branched chain,saturated, monovalent hydrocarbon residue containing 1 to 10 carbonatoms. The term “lower alkyl” denotes a straight or branched chainhydrocarbon residue containing 1 to 6 carbon atoms. “C₁₋₁₀ alkyl” asused herein refers to an alkyl composed of 1 to 10 carbons. Examples ofalkyl groups include, but are not limited to, lower alkyl groups includemethyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, t-butyl or pentyl,isopentyl, neopentyl, hexyl, heptyl, and octyl.

When the term “alkyl” is used as a suffix following another term, as in“phenylalkyl,” or “hydroxyalkyl,” this is intended to refer to an alkylgroup, as defined above, being substituted with one to two substituentsselected from the other specifically-named group. Thus, for example,“phenylalkyl” denotes the radical R′R″-, wherein R′ is a phenyl radical,and R″ is an alkylene radical as defined herein with the understandingthat the attachment point of the phenylalkyl moiety will be on thealkylene radical. Examples of arylalkyl radicals include, but are notlimited to, benzyl, phenylethyl, 3-phenylpropyl. The terms “arylalkyl”or “aralkyl” are interpreted similarly except R′ is an aryl radical. Theterms “(het)arylalkyl” or “(het)aralkyl” are interpreted similarlyexcept R′ is optionally an aryl or a heteroaryl radical.

The terms “haloalkyl” or “halo-lower alkyl” or “lower haloalkyl” refersto a straight or branched chain hydrocarbon residue containing 1 to 6carbon atoms wherein one or more carbon atoms are substituted with oneor more halogen atoms.

The term “alkylene” or “alkylenyl” as used herein denotes a divalentsaturated linear hydrocarbon radical of 1 to 10 carbon atoms (e.g.,(CH₂)_(n)) or a branched saturated divalent hydrocarbon radical of 2 to10 carbon atoms (e.g., —CHMe- or —CH₂CH(i-Pr)CH₂—), unless otherwiseindicated. Except in the case of methylene, the open valences of analkylene group are not attached to the same atom. Examples of alkyleneradicals include, but are not limited to, methylene, ethylene,propylene, 2-methyl-propylene, 1,1-dimethyl-ethylene, butylene,2-ethylbutylene.

The term “alkoxy” as used herein means an —O-alkyl group, wherein alkylis as defined above such as methoxy, ethoxy, n-propyloxy, i-propyloxy,n-butyloxy, i-butyloxy, t-butyloxy, pentyloxy, hexyloxy, including theirisomers. “Lower alkoxy” as used herein denotes an alkoxy group with a“lower alkyl” group as previously defined. “C₁₋₁₀ alkoxy” as used hereinrefers to an-O-alkyl wherein alkyl is C₁₋₁₀.

The term “aryl” denotes a monovalent aromatic carbocyclic mono- orbicyclic ring system comprising 6 to 10 carbon ring atoms. Examples ofaryl moieties include phenyl and naphthyl.

The term “PCy₃” refers to a phosphine trisubstituted with three cyclicmoieties.

The terms “haloalkoxy” or “halo-lower alkoxy” or “lower haloalkoxy”refers to a lower alkoxy group, wherein one or more carbon atoms aresubstituted with one or more halogen atoms.

The term “hydroxyalkyl” as used herein denotes an alkyl radical asherein defined wherein one to three hydrogen atoms on different carbonatoms is/are replaced by hydroxyl groups.

The terms “alkylsulfonyl” and “arylsulfonyl” as used herein refers to agroup of formula —S(═O)₂R wherein R is alkyl or aryl respectively andalkyl and aryl are as defined herein. The term “heteroalkylsulfonyl” asused herein refers herein denotes a group of formula —S(═O)₂R wherein Ris “heteroalkyl” as defined herein.

The terms “alkylsulfonylamino” and “arylsulfonylamino” as used hereinrefers to a group of formula —NR′S(═O)₂R wherein R is alkyl or arylrespectively, R′ is hydrogen or C₁₋₃ alkyl, and alkyl and aryl are asdefined herein.

The term “cycloalkyl” as used herein refers to a saturated carbocyclicring containing 3 to 8 carbon atoms, i.e. cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. “C₃₋₇ cycloalkyl” or“lower cycloalkyl” as used herein refers to an cycloalkyl composed of 3to 7 carbons in the carbocyclic ring.

The term carboxy-alkyl as used herein refers to an alkyl moiety whereinone, hydrogen atom has been replaced with a carboxyl with theunderstanding that the point of attachment of the heteroalkyl radical isthrough a carbon atom. The term “carboxy” or “carboxyl” refers to a—CO₂H moiety.

The term “heteroaryl” or “heteroaromatic” as used herein means amonocyclic or bicyclic radical of 5 to 12 ring atoms having at least onearomatic or partially unsaturated ring containing four to eight atomsper ring, incorporating one or more N, O, or S heteroatoms, theremaining ring atoms being carbon, with the understanding that theattachment point of the heteroaryl radical will be on an aromatic orpartially unsaturated ring. As well known to those skilled in the art,heteroaryl rings have less aromatic character than their all-carboncounter parts. Thus, for the purposes of the invention, a heteroarylgroup need only have some degree of aromatic character. Heteroaryl maybe optionally substituted as defined directly below. Examples ofheteroaryl moieties include monocyclic aromatic heterocycles having 5 to6 ring atoms and 1 to 3 heteroatoms include, but is not limited to,pyridinyl, pyrimidinyl, pyrazinyl, oxazinyl, pyrrolyl, pyrazolyl,imidazolyl, oxazolyl, 4,5-Dihydro-oxazolyl,5,6-Dihydro-4H-[1,3]oxazolyl, isoxazole, thiazole, isothiazole,triazoline, thiadiazole and oxadiaxoline which can optionally besubstituted with one or more, preferably one or two substituentsselected from hydroxy, cyano, alkyl, alkoxy, thio, lower haloalkoxy,alkylthio, halo, lower haloalkyl, alkylsulfinyl, alkylsulfonyl, halogen,amino, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, anddialkylaminoalkyl, nitro, alkoxycarbonyl and carbamoyl, alkylcarbamoyl,dialkylcarbamoyl, arylcarbamoyl, alkylcarbonylamino andarylcarbonylamino. Examples of bicyclic moieties include, but are notlimited to, quinolinyl, isoquinolinyl, benzofuryl, benzothiophenyl,benzoxazole, benzisoxazole, benzothiazole, naphthyridinyl,5,6,7,8-Tetrahydro-[1,6]naphthyridinyl, and benzisothiazole. Bicyclicmoieties can be optionally substituted on either ring, however the pointof attachment is on a ring containing a heteroatom.

The term “heterocyclyl”, “heterocycloalkyl” or “heterocycle” as usedherein denotes a monovalent saturated cyclic radical, consisting of oneor more rings, preferably one to two rings, including spirocyclic ringsystems, of three to eight atoms per ring, incorporating one or morering heteroatoms (chosen from N,O or S(O)₀₋₂), and which can optionallybe independently substituted with one or more, preferably one or twosubstituents selected from hydroxy, oxo, cyano, lower alkyl, loweralkoxy, lower haloalkoxy, alkylthio, halo, lower haloalkyl,hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl,arylsulfonyl, alkylaminosulfonyl, arylaminosulfonyl, alkylsulfonylamino,arylsulfonylamino, alkylaminocarbonyl, arylaminocarbonyl,alkylcarbonylamino, arylcarbonylamino, and ionic forms thereof, unlessotherwise indicated. Examples of heterocyclic radicals include, but arenot limited to, morpholinyl, piperazinyl, piperidinyl, azetidinyl,pyrrolidinyl, hexahydroazepinyl, oxetanyl, tetrahydrofuranyl,tetrahydrothiophenyl, oxazolidinyl, thiazolidinyl, isoxazolidinyl,tetrahydropyranyl, thiomorpholinyl, quinuclidinyl and imidazolinyl, andionic forms thereof. Examples may also be bicyclic, such as, forexample, 3,8-diaza-bicyclo[3.2.1]octane, 2,5-diaza-bicyclo[2.2.2]octane,or octahydro-pyrazino[2,1-c][1,4]oxazine.

Inhibitors of Btk

The present application discloses6-(2-Hydroxymethyl-phenyl)-2-methyl-2H-pyridazin-3-one derivativesaccording to generic Formula I, wherein the variables are defined asdescribed herein:

The phrase “as defined herein” refers to the broadest definition foreach group as provided in the Summary of the Invention, the DetailedDescription, or the broadest claim. In all other aspects, variations andembodiments provided, substituents which can be present in eachembodiment and which are not explicitly defined retain the broadestdefinition provided in the Summary of the Invention, the DetailedDescription, or the broadest claim.

The compounds of generic Formula I inhibit Bruton's tyrosine kinase(Btk). Activation of Btk by upstream kinases results in activation ofphospholipase-Cγ which, in turn, stimulates release of pro-inflammatorymediators. The compounds of generic Formula I, incorporating side chainsof the

ring systems, exhibit unexpectedly enhanced inhibitory activity comparedto analogues with other side chains. Notably, fluorine substitution onthe unsaturated side chains produces an unexpected approximately5-10-fold increase in potency in human whole blood. Furthermore, thefluorinated sidechain provides the increase in potency while, inconjunction with the pyridazinone core of the molecules, the moleculesgenerally have unexpectedly improved safety profiles compared to thosewith pyridinone cores. Specifically, the pyridazinone core molecules donot undergo unacceptable levels of covalent binding due to reactivemetabolites during metabolism. Compounds of Formula I are useful in thetreatment of arthritis and other anti-inflammatory and auto-immunediseases. Compounds according to Formula I are, accordingly, useful forthe treatment of arthritis. Compounds of Formula I are useful forinhibiting Btk in cells and for modulating B-cell development. Thepresent invention further comprises pharmaceutical compositionscontaining compounds of Formula I admixed with pharmaceuticallyacceptable carrier, excipients or diluents.

The application provides a compound of Formula I,

wherein:

is either a single or double bond;X is either CH, CH₂, or N;

R is H, -R¹, -R¹-R²-R³, -R¹-R³, or -R²-R³;

R¹ is aryl, heteroaryl, bicyclic heteroaryl, cycloalkyl, orheterocycloalkyl, each of which is optionally substituted with one ormore lower alkyl, hydroxy, hydroxy lower alkyl, lower alkoxy, halo,nitro, amino, amido, cyano, oxo, or lower haloalkyl;

R² is —C(═O), —C(═O)O, —C(═O)NR^(2′), —NHC(═O)O, —C(R^(2′))₂, —O, —S,—C(═NH)NR^(2′), or —S(═O)₂;

each R^(2′) is independently H or lower alkyl;

R³ is H or R⁴;

R⁴ is lower alkyl, lower haloalkyl, lower alkoxy, amino, lower alkylamino, cycloalkyl amino, lower dialkyl amino, aryl, arylalkyl,alkylaryl, heteroaryl, alkyl heteroaryl, heteroaryl alkyl, cycloalkyl,alkyl cycloalkyl, cycloalkyl alkyl, heterocycloalkyl, alkylheterocycloalkyl, heterocycloalkyl alkyl, bicyclic cycloalkyl, bicyclicheterocycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, or bicyclicspiroheterocycloalkyl, each of which is optionally substituted with oneor more lower alkyl, halo, lower alkyl amino, lower dialkyl amino,hydroxy, hydroxy lower alkyl, lower alkoxy, lower alkanoyl, halo, nitro,amino, amido, acyl, cyano, oxo, sulfonyl, lower alkyl sulfonyl,guanidino, hydroxyl amino, carboxy, carbamoyl, carbamate, halo loweralkoxy, heterocycloalkyl, or halo lower alkyl, wherein two lower alkylgroups may together form a ring;

Y⁴ is Y^(4a), Y^(4b), Y^(4c), or Y^(4d);

Y^(4a) is H or halogen;

Y^(4b) is lower alkyl, optionally substituted with one or moresubstituents selected from the group consisting of lower haloalkyl,halogen, hydroxy, amino, cyano, and lower alkoxy;

Y^(4c) is lower cycloalkyl, optionally substituted with one or moresubstituents selected from the group consisting of lower alkyl, lowerhaloalkyl, halogen, hydroxy, amino, cyano, and lower alkoxy; and

Y^(4d) is amino, optionally substituted with one or more lower alkyl,alkoxy lower alkyl, or hydroxy lower alkyl;

or a pharmaceutically acceptable salt thereof.

Further it is to be understood that every embodiment relating to aspecific residue R, X and Y⁴ as disclosed herein may be combined withany other embodiment relating to another residue R, X and Y⁴ asdisclosed herein.

The application provides a compound of Formula I, wherein

is a double bond; and

X is N.

The application provides a compound of Formula I, wherein

is a single bond; and

X is CH₂.

The application provides a compound of Formula I, wherein

is a double bond;

X is N; R is -R¹-R²-R³;

R¹ is pyridyl;

R² is —S(═O)₂, R³ is R⁴; and

R⁴ is lower alkyl.

The application provides a compound of Formula I, wherein

is a double bond;

X is N; R is -R¹-R²-R³;

R¹ is pyridyl;

R² is —C(CH₃)₂; R³ is R⁴; and

R⁴ is lower alkyl amino, lower dialkyl amino, or heterocycloalkyloptionally substituted with one or more lower alkyl.

The application provides a compound of Formula I, wherein

is a double bond;

X is N; R is -R¹-R²-R³;

R¹ is phenyl or pyridyl;

R² is -—C(═O); R³ is R⁴; and

R⁴ is morpholine or piperazine, optionally substituted with one or morelower alkyl.

The application provides a compound of Formula I, wherein

is a double bond;

X is N; and

Y⁴ is tert-butyl.

The application provides a compound of Formula I, wherein

is a double bond;

X is CH; and Y⁴ is

wherein, Y⁵ and Y⁶ are independently H, lower alkyl, or lower haloalkyl.

The application provides a compound of Formula I, wherein

is a double bond;

X is N; and Y⁴ is

wherein, Y⁵ is H, halogen, lower alkyl or lower haloalkyl.

The application provides a compound of Formula I, wherein

is a double bond;

X is N; and Y⁴ is

wherein, Y⁵ and Y⁶ are independently H or lower alkyl.

The application provides a compound of Formula I, wherein

is a double bond;

X is N;

Y⁴ is tert-butyl;

R is -R¹-R³;

R¹ is pyridyl or pyrazolopyrazine;

R³ is R⁴; and

R⁴ is optionally substituted lower alkyl, heterocycloalkyl, or alkylheterocycloalkyl.

The application provides a compound of Formula I, wherein

is a double bond;

X is N;

Y⁴ is tert-butyl;

R is -R¹-R²-R³;

R¹ is pyridyl;

R² is —C(CH₃)₂; R³ is R⁴; and

R⁴ is lower alkyl amino, lower dialkyl amino, or heterocycloalkyloptionally substituted with one or more lower alkyl.

The application provides a compound of Formula I, wherein

is a double bond;

X is N;

Y⁴ is tert-butyl;

R is -R¹-R²-R³;

R¹ is pyridyl;

R² is —C(═O); R³ is R⁴; and

R⁴ is optionally substituted heterocycloalkyl or bicyclicspiroheterocycloalkyl.

The application provides a compound of Formula I, wherein

is a double bond;

X is N;

Y⁴ is tert-butyl;

R is -R¹-R²-R³;

R¹ is pyridyl;

R² is —C(═O); R³ is R⁴; and

R⁴ is optionally substituted morpholine or piperazine.

The application provides a compound of Formula I selected from the groupconsisting of:

-   6-tert-Butyl-2-(3-{5-[5-(1-ethylamino-1-methyl-ethyl)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-2-hydroxymethyl-phenyl)-8-fluoro-2H-phthalazin-1-one;-   6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one;-   6-tert-Butyl-8-fluoro-2-{2-hydroxymethyl-3-[5-(5-methanesulfonyl-pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl]-phenyl}-2H-phthalazin-1-one;-   6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{5-[5-(3-methoxy-azetidin-1-ylmethyl)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one;-   6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(8-methyl-3,8-diaza-bicyclo[3.2.1]oct-3-ylmethyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one;-   6-tert-Butyl-2-(3-{5-[5-(2-dimethylamino-1,1-dimethyl-ethoxy)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-2-hydroxymethyl-phenyl)-8-fluoro-2H-phthalazin-1-one;-   2-{3-[5-(5-Azetidin-1-ylmethyl-pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl]-2-hydroxymethyl-phenyl}-6-tert-butyl-8-fluoro-2H-phthalazin-1-one;-   6-tert-Butyl-2-{3-[5-(5-dimethylaminomethyl-pyridin-2-ylamino)-1-methyl-1-6-oxo-1,6-dihydro-pyridazin-3-yl]-2-hydroxymethyl-phenyl}-8-fluoro-2H-phthalazin-1-one;-   6-tert-Butyl-2-(3-{5-[(1R,5S)-5-(3,8-diaza-bicyclo[3.2.1]oct-8-yl)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-2-hydroxymethyl-phenyl)-8-fluoro-2H-phthalazin-1-one;-   6-{6-[3-(6-tert-Butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-2-methyl-3-oxo-2,3-dihydro-pyridazin-4-ylamino}-N,N-dimethyl-nicotinamide;-   6-tert-Butyl-8-fluoro-2-{2-hydroxymethyl-3-[1-methyl-6-oxo-5-(5-trifluoromethyl-pyrazin-2-ylamino)-1,6-dihydro-pyridazin-3-yl]-phenyl}-2H-phthalazin-1-one;-   6-tert-Butyl-8-fluoro-2-(3-{5-[5-(2-hydroxy-1,1-dimethyl-ethoxy)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-2-hydroxymethyl-phenyl)-2H-phthalazin-1-one;-   2-(3-{5-[5-(2-Azetidin-1-yl-1,1-dimethyl-ethoxy)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-2-hydroxymethyl-phenyl)-6-tert-butyl-8-fluoro-2H-phthalazin-1-one;-   6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{5-[5-(2-hydroxy-2-methyl-propoxy)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one;-   2-[8-Fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-1-oxo-1,2-dihydro-isoquinolin-6-yl]-2-methyl-propionitrile;-   6-tert-Butyl-8-fluoro-2-(3-{5-[5-((S)-2-hydroxy-3-methoxy-propoxy)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-2-hydroxymethyl-phenyl)-2H-phthalazin-1-one;-   6-tert-Butyl-8-fluoro-2-(3-{5-[5-((R)-2-hydroxy-3-methoxy-propoxy)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-2-hydroxymethyl-phenyl)-2H-phthalazin-1-one;-   6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-((S)-1-methyl-pyrrolidin-2-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one;-   6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-((R)-1-methyl-pyrrolidin-2-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one;-   6-{6-[3-(6-tert-Butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-2-methyl-3-oxo-2,3-dihydro-pyridazin-4-ylamino}-N,N-dimethyl-nicotinamide;-   6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{5-[5-(4-hydroxy-4-methyl-piperidine-1-carbonyl)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one;-   6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(6-methyl-2,6-diaza-spiro[3.3]hept-2-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one;-   6-tert-Butyl-2-{3-[5-(5-ethanesulfonyl-pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl]-2-hydroxymethyl-phenyl}-8-fluoro-2H-phthalazin-1-one;-   6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-6-oxo-5-[5-(propane-2-sulfonyl)-pyridin-2-ylamino]-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one;-   6-tert-Butyl-8-fluoro-2-(3-{5-[5-(2-hydroxy-ethylsulfanyl)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-2-hydroxymethyl-phenyl)-2H-phthalazin-1-one;-   6-tert-Butyl-8-fluoro-2-(3-{5-[5-(2-hydroxy-ethanesulfonyl)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-2-hydroxymethyl-phenyl)-2H-phthalazin-1-one;-   6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{5-[5-(4-isopropyl-piperazin-1-yl)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one;-   6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(1-methyl-pyrrolidin-3-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one;-   6-tert-Butyl-8-fluoro-2-{2-hydroxymethyl-3-[5-(1′-isopropyl-1′,2′,3′,4′,5′,6′-hexahydro-[3,4′]bipyridinyl-6-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl]-phenyl}-2H-phthalazin-1-one;-   6-tert-Butyl-2-{3-[5-(1′-ethyl-1′,2′,3′,4′,5′,6′-hexahydro-[3,4]bipyridinyl-6-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl]-2-hydroxymethyl-phenyl}-8-fluoro-2H-phthalazin-1-one;-   6-tert-Butyl-2-{3-[5-(1,5-dimethyl-1H-pyrazol-3-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl]-2-hydroxymethyl-phenyl}-8-fluoro-2H-phthalazin-1-one;-   6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-((S)-1-methyl-pyrrolidin-3-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one;-   6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-((R)-1-methyl-pyrrolidin-3-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one;-   6-tert-Butyl-8-fluoro-2-{2-hydroxymethyl-3-[1-methyl-5-(4-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-ylamino)-6-oxo-1,6-dihydro-pyridazin-3-yl]-phenyl}-2H-phthalazin-1-one;-   6-tert-Butyl-2-{3-[5-(5-cyclobutylaminomethyl-pyrazin-2-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl]-2-hydroxymethyl-phenyl}-8-fluoro-2H-phthalazin-1-one;-   6-tert-Butyl-2-(3-{5-[5-(2-dimethylamino-ethoxy)-pyrazin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-2-hydroxymethyl-phenyl)-8-fluoro-2H-phthalazin-1-one;-   6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methyl-piperazin-1-ylmethyl)-pyrazin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one;-   6-tert-Butyl-2-(3-{5-[5-(2-dimethylamino-1,1-dimethyl-ethoxy)-pyrazin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-2-hydroxymethyl-phenyl)-8-fluoro-2H-phthalazin-1-one;-   6-tert-Butyl-2-(3-{5-[6-(2-dimethylamino-1,1-dimethyl-ethoxy)-pyridazin-3-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-2-hydroxymethyl-phenyl)-8-fluoro-2H-phthalazin-1-one;-   6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[6-(1-methyl-piperidin-4-yl)-pyridazin-3-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one;-   6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one;-   6-tert-Butyl-8-fluoro-2-[2-hydroxymethyl-3-(5-{5-[(2-methoxy-ethylamino)-methyl]-pyridin-2-ylamino}-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl)-phenyl]-2H-phthalazin-1-one;-   6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(1S,4S)-5-methyl-2,5-diaza-bicyclo[2.2.1]hept-2-ylmethyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one;-   6-tert-Butyl-8-fluoro-2-{2-hydroxymethyl-3-[5-(5-{[(2-methoxy-ethyl)-methyl-amino]-methyl}-pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl]-phenyl}-2H-phthalazin-1-one;-   6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[6-(4-methyl-piperazin-1-yl)-pyridazin-3-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one;-   6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[6-((1S,4S)-5-methyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-pyridazin-3-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one;-   2-(3-{5-[5-(Azetidine-1-carbonyl)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-2-hydroxymethyl-phenyl)-6-tert-butyl-8-fluoro-2H-phthalazin-1-one;-   6-tert-Butyl-2-(3-{5-[5-(1,1-dioxo-1λ6-thiomorpholine-4-carbonyl)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-2-hydroxymethyl-phenyl)-8-fluoro-2H-phthalazin-1-one;-   6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(2-oxa-6-aza-spiro[3.3]heptane-6-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one;-   6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(6-methyl-2,6-diaza-spiro[3.3]heptane-2-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one;-   6-{6-[3-(6-tert-Butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-2-methyl-3-oxo-2,3-dihydro-pyridazin-4-ylamino}-N-(2-dimethylamino-ethyl)-nicotinamide;-   6-{6-[3-(6-tert-Butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-2-methyl-3-oxo-2,3-dihydro-pyridazin-4-ylamino}-N-(2-hydroxy-ethyl)-N-methyl-nicotinamide;-   1-(6-{6-[3-(6-tert-Butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-2-methyl-3-oxo-2,3-dihydro-pyridazin-4-ylamino}-pyridine-3-carbonyl)-azetidine-3-carbonitrile;-   6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{5-[5-(3-hydroxy-pyrrolidine-1-carbonyl)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one;-   6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{5-[5-(4-hydroxy-piperidine-1-carbonyl)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one;-   6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methyl-piperazin-1-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one;-   6-tert-Butyl-2-(3-{5-[5-((S)-1,2-dihydroxy-ethyl)-pyrazin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-2-hydroxymethyl-phenyl)-8-fluoro-2H-phthalazin-1-one;-   2-{3-[5-(5-Azetidin-1-ylmethyl-1-methyl-1H-pyrazol-3-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl]-2-hydroxymethyl-phenyl}-6-tert-butyl-8-fluoro-2H-phthalazin-1-one;-   6-tert-Butyl-8-fluoro-2-{2-hydroxymethyl-3-[1-methyl-5-(5-methyl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazin-2-ylamino)-6-oxo-1,6-dihydro-pyridazin-3-yl]-phenyl}-2H-phthalazin-1-one;-   6-tert-Butyl-8-fluoro-2-{2-hydroxymethyl-3-[1-methyl-5-(5-oxetan-3-yl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazin-2-ylamino)-6-oxo-1,6-dihydro-pyridazin-3-yl]-phenyl}-2H-phthalazin-1-one;-   6-tert-Butyl-8-fluoro-2-{3-[5-(1′,2′,3′,4′,5′,6′-hexahydro-[3,4]bipyridinyl-6-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl]-2-hydroxymethyl-phenyl}-2H-phthalazin-1-one;-   6-tert-Butyl-8-fluoro-2-{2-hydroxymethyl-3-[5-(1′-methanesulfonyl-1′,2′,3′,4′,5′,6′-hexahydro-[3,4]bipyridinyl-6-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl]-phenyl}-2H-phthalazin-1-one;-   2-{3-[5-(1′-Acetyl-1′,2′,3′,4′,5′,6′-hexahydro-[3,4]bipyridinyl-6-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl]-2-hydroxymethyl-phenyl}-6-tert-butyl-8-fluoro-2H-phthalazin-1-one;-   6-tert-Butyl-8-fluoro-2-{2-hydroxymethyl-3-[5-(4-hydroxy-4-methyl-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl]-phenyl}-2H-phthalazin-1-one;-   6-tert-Butyl-8-fluoro-2-{2-hydroxymethyl-3-[5-(4-hydroxy-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl]-phenyl}-2H-phthalazin-1-one;-   6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-((1R,5S)-3-methyl-3,8-diaza-bicyclo[3.2.1]oct-8-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one;-   6-tert-Butyl-8-fluoro-2-{2-hydroxymethyl-3-[1-methyl-5-(1′-methyl-1′,2′,3′,4′,5′,6′-hexahydro-[3,4]bipyridinyl-6-ylamino)-6-oxo-1,6-dihydro-pyridazin-3-yl]-phenyl}-2H-phthalazin-1-one;-   6-tert-Butyl-2-(3-{5-[1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-2-hydroxymethyl-phenyl)-8-fluoro-2H-phthalazin-1-one;-   6-tert-Butyl-2-(3-{5-[5-(4-ethyl-piperazin-1-yl)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-2-hydroxymethyl-phenyl)-8-fluoro-2H-phthalazin-1-one;-   6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{5-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one;-   2-(8-Fluoro-2-{2-hydroxymethyl-3-[1-methyl-5-(1′-methyl-1′,2′,3′,4′,5′,6′-hexahydro-[3,4]bipyridinyl-6-ylamino)-6-oxo-1,6-dihydro-pyridazin-3-yl]-phenyl}-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-methyl-propionitrile;-   2-(2-{3-[5-(5-Azetidin-1-ylmethyl-1-methyl-1H-pyrazol-3-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl]-2-hydroxymethyl-phenyl}-8-fluoro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-methyl-propionitrile;-   2-[2-(3-{5-[5-(2-Azetidin-1-yl-1,1-dimethyl-ethoxy)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-2-hydroxymethyl-phenyl)-8-fluoro-1-oxo-1,2-dihydro-isoquinolin-6-yl]-2-methyl-propionitrile;-   2-(8-Fluoro-2-{2-hydroxymethyl-3-[1-methyl-5-(5-methyl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazin-2-ylamino)-6-oxo-1,6-dihydro-pyridazin-3-yl]-phenyl}-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-methyl-propionitrile;-   6-(6-{3-[6-(Cyano-dimethyl-methyl)-8-fluoro-1-oxo-1H-isoquinolin-2-yl]-2-hydroxymethyl-phenyl}-2-methyl-3-oxo-2,3-dihydro-pyridazin-4-ylamino)-N,N-dimethyl-nicotinamide;-   2-[8-Fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-((S)-1-methyl-pyrrolidin-2-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-1-oxo-1,2-dihydro-isoquinolin-6-yl]-2-methyl-propionitrile;-   2-[8-Fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-((S)-1-methyl-pyrrolidin-3-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-1-oxo-1,2-dihydro-isoquinolin-6-yl]-2-methyl-propionitrile;-   2-[2-(3-{5-[5-(2-Azetidin-1-yl-1,1-dimethyl-ethoxy)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-2-hydroxymethyl-phenyl)-8-fluoro-1-oxo-1,2,3,4-tetrahydro-isoquinolin-6-yl]-2-methyl-propionitrile;-   2-(8-Fluoro-2-{2-hydroxymethyl-3-[1-methyl-5-(5-oxetan-3-yl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazin-2-ylamino)-6-oxo-1,6-dihydro-pyridazin-3-yl]-phenyl}-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-methyl-propionitrile;-   6-tert-Butyl-8-fluoro-2-{2-hydroxymethyl-3-[1-methyl-5-(1′-oxetan-3-yl-1′,2′,3′,4′,5′,6′-hexahydro-[3,4]bipyridinyl-6-ylamino)-6-oxo-1,6-dihydro-pyridazin-3-yl]-phenyl}-2H-phthalazin-1-one;-   2-(8-Fluoro-2-{2-hydroxymethyl-3-[1-methyl-5-(1′-oxetan-3-yl-1′,2′,3′,4′,5′,6′-hexahydro-[3,4]bipyridinyl-6-ylamino)-6-oxo-1,6-dihydro-pyridazin-3-yl]-phenyl}-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-methyl-propionitrile;-   6-tert-Butyl-2-{3-[5-(5-ethyl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazin-2-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl]-2-hydroxymethyl-phenyl}-8-fluoro-2H-phthalazin-1-one;-   2-(2-{3-[5-(5-Ethyl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazin-2-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl]-2-hydroxymethyl-phenyl}-8-fluoro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-methyl-propionitrile;-   6-tert-Butyl-2-[3-(5-{5-[(1S,4S)-1-(2,5-diaza-bicyclo[2.2.1]hept-2-yl)methyl]-pyridin-2-ylamino}-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl)-2-hydroxymethyl-phenyl]-8-fluoro-2H-phthalazin-1-one;-   6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{5-[5-(4-hydroxy-4-methyl-piperidin-1-ylmethyl)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one;-   4-(6-{6-[3-(6-tert-Butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-2-methyl-3-oxo-2,3-dihydro-pyridazin-4-ylamino}-pyridin-3-yl)-piperazine-1-carboxylic    acid ethyl ester;-   8-Fluoro-6-(2-fluoro-1,1-dimethyl-ethyl)-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-isoquinolin-1-one;-   6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-((1S,4S)-5-methyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-pyrazin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one;-   2-[8-Fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-((R)-1-methyl-pyrrolidin-3-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-1-oxo-1,2-dihydro-isoquinolin-6-yl]-2-methyl-propionitrile;    and-   6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-6-oxo-5-[1′-(2,2,2-trifluoro-ethyl)-1′,2′,3′,4′,5′,6′-hexahydro-[3,4]bipyridinyl-6-ylamino]-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one.

The application provides a method for treating an inflammatory and/orautoimmune condition comprising administering to a patient in needthereof a therapeutically effective amount of the compound of Formula I.

The application provides a method for treating rheumatoid arthritiscomprising administering to a patient in need thereof a therapeuticallyeffective amount of the compound of Formula I.

The application provides a method for treating asthma comprisingadministering to a patient in need thereof a therapeutically effectiveamount of the compound of Formula I.

The application provides a pharmaceutical composition comprising thecompound of Formula I.

The application provides a pharmaceutical composition comprising thecompound of Formula I, admixed with at least one pharmaceuticallyacceptable carrier, excipient or diluent.

The application provides a use of the compound of formula I in themanufacture of a medicament for the treatment of an inflammatorydisorder.

The application provides a use of the compound of formula I in themanufacture of a medicament for the treatment of an autoimmune disorder.

The application provides a use of the compound of formula I in themanufacture of a medicament for the treatment of rheumatoid arthritis.

The application provides a use of the compound of formula I in themanufacture of a medicament for the treatment of asthma.

The application provides the use of a compound as described above forthe treatment of inflammatory and/or autoimmune condition.

The application provides the use of a compound as described above forthe treatment of rheumatoid arthritis.

The application provides the use of a compound as described above forthe treatment of asthma.

The application provides a compound as described above for use in thetreatment of inflammatory and/or autoimmune condition.

The application provides a compound as described above for use in thetreatment of rheumatoid arthritis.

The application provides a compound as described above for use in thetreatment of asthma.

The application provides a compound, method, or composition as describedherein.

The application provides a compound of Formula I′,

wherein:

R is H, -R¹, -R¹-R²-R³, -R¹-R³, or -R²-R³;

R¹ is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each of whichis optionally substituted with one or more lower alkyl, hydroxy, hydroxylower alkyl, lower alkoxy, halo, nitro, amino, amido, cyano, oxo, orlower haloalkyl;

R² is —C(═O), —C(═O)O, —C(═O)NR^(2′), —NHC(═O)O, —C(R^(2′))₂, —O,—C(═NH)NR^(2′), or —S(═O)₂;

each R^(2′) is independently H or lower alkyl;

R³ is H or R⁴;

R⁴ is lower alkyl, lower haloalkyl, lower alkoxy, amino, lower alkylamino, lower dialkyl amino, aryl, arylalkyl, alkylaryl, heteroaryl,alkyl heteroaryl, heteroaryl alkyl, cycloalkyl, alkyl cycloalkyl,cycloalkyl alkyl, heterocycloalkyl, alkyl heterocycloalkyl,heterocycloalkyl alkyl, bicyclic cycloalkyl, bicyclic heterocycloalkyl,spirocycloalkyl, or spiroheterocycloalkyl, each of which is optionallysubstituted with one or more lower alkyl, halo, lower alkyl amino, lowerdialkyl amino, hydroxy, hydroxy lower alkyl, lower alkoxy, halo, nitro,amino, amido, acyl, cyano, oxo, guanidino, hydroxyl amino, carboxy,carbamoyl, carbamate, halo lower alkoxy, or halo lower alkyl, whereintwo lower alkyl groups may together form a ring;

Y⁴ is Y^(4a), Y^(4b), Y^(4c), or Y^(4d);

Y^(4a) is H or halogen;

Y^(4b) is lower alkyl, optionally substituted with one or moresubstituents selected from the group consisting of lower haloalkyl,halogen, hydroxy, amino, cyano, and lower alkoxy;

Y^(4c) is lower cycloalkyl, optionally substituted with one or moresubstituents selected from the group consisting of lower alkyl, lowerhaloalkyl, halogen, hydroxy, amino, cyano, and lower alkoxy; and

Y^(4d) is amino, optionally substituted with one or more lower alkyl,alkoxy lower alkyl, or hydroxy lower alkyl;

or a pharmaceutically acceptable salt thereof.

In one variation of Formula I′, Y⁴ is tert-butyl, dimethyl amino,cycloproplyl, or iso-propyl.

In one variation of Formula I′, Y⁴ is tert-butyl.

In one variation of Formula I′, Y⁴ is dimethyl amino.

In one variation of Formula I′, Y⁴ is cycloproplyl.

In one variation of Formula I′, Y⁴ is iso-propyl.

In one variation of Formula I′, R is -R¹-R³;

R¹ is pyridyl;

R³ is R⁴; and

R⁴ is heterocycloalkyl, optionally substituted with lower alkyl.

In one variation of Formula I′, R is -R¹-R²-R³;

R¹ is pyridyl;

R² is —C(CH₃)₂; R³ is R⁴; and

R⁴ is lower alkyl amino, lower dialkyl amino, or heterocycloalkyloptionally substituted with one or more lower alkyl.

In one variation of Formula I′,

R is -R¹-R²-R³;

R¹ is phenyl or pyridyl;

R² is —C(═O); R³ is R⁴; and

R⁴ is morpholine or piperazine, optionally substituted with one or morelower alkyl.

In one variation of Formula I′, R¹ is pyridyl;

R³ is R⁴; and

R⁴ is —S(═O)₂R^(4′), wherein R^(4′) is lower alkyl.

In one variation of Formula I′, Y⁴ is

wherein, Y⁵ is H, halogen, lower alkyl or lower haloalkyl.

In one variation of Formula I′, Y⁴ is

wherein, Y⁵ and Y⁶ are independently H, lower alkyl, or lower haloalkyl.

In one variation of Formula I′, Y⁴ is

wherein, Y⁵ and Y⁶ are independently H or lower alkyl.

In one variation of Formula I′, Y⁴ is

wherein, Y⁵ and Y⁶ are independently H, lower alkyl, or lower haloalkyl.

In one variation of Formula I′, Y⁴ is tert-butyl;

R is -R¹-R³;

R¹ is pyridyl;

R³ is R⁴; and

R⁴ is —S(═O)₂R^(4′), wherein R^(4′) is lower alkyl.

In one variation of Formula I′, Y⁴ is tert-butyl;

R is -R¹-R²-R³;

R¹ is pyridyl;

R² is —C(CH₃)₂; R³ is R⁴; and

R⁴ is lower alkyl amino, lower dialkyl amino, or heterocycloalkyloptionally substituted with one or more lower alkyl.

In one variation of Formula I′, Y⁴ is tert-butyl;

R is -R¹-R²-R³;

R¹ is pyridyl;

R² is —C(═O); R³ is R⁴; and

R⁴ is morpholine or piperazine, optionally substituted with one or morelower alkyl.

In one variation of Formula I′, Y⁴ is tert-butyl;

R is -R¹-R³;

R¹ is pyridyl;

R³ is R⁴; and

R⁴ is heterocycloalkyl, optionally substituted with lower alkyl.

The application provides the compounds of Formula I′ selected from thegroup consisting of:

-   6-tert-Butyl-2-(3-{5-[5-(1-ethylamino-1-methyl-ethyl)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-2-hydroxymethyl-phenyl)-8-fluoro-2H-phthalazin-1-one;-   6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one;-   6-tert-Butyl-8-fluoro-2-{2-hydroxymethyl-3-[5-(5-methanesulfonyl-pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl]-phenyl}-2H-phthalazin-1-one;-   6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{5-[5-(3-methoxy-azetidin-1-ylmethyl)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one;-   6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(8-methyl-3,8-diaza-bicyclo[3.2.1]oct-3-ylmethyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one;-   6-tert-Butyl-2-(3-{5-[5-(2-dimethylamino-1,1-dimethyl-ethoxy)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-2-hydroxymethyl-phenyl)-8-fluoro-2H-phthalazin-1-one;-   2-{3-[5-(5-Azetidin-1-ylmethyl-pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl]-2-hydroxymethyl-phenyl}-6-tert-butyl-8-fluoro-2H-phthalazin-1-one;-   6-tert-Butyl-2-{3-[5-(5-dimethylaminomethyl-pyridin-2-ylamino)-1-methyl-1-6-oxo-1,6-dihydro-pyridazin-3-yl]-2-hydroxymethyl-phenyl}-8-fluoro-2H-phthalazin-1-one;-   6-tert-Butyl-2-(3-{5-[(1R,5S)-5-(3,8-diaza-bicyclo[3.2.1]oct-8-yl)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-2-hydroxymethyl-phenyl)-8-fluoro-2H-phthalazin-1-one;-   6-{6-[3-(6-tert-Butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-2-methyl-3-oxo-2,3-dihydro-pyridazin-4-ylamino}-N,N-dimethyl-nicotinamide;    and-   6-tert-Butyl-8-fluoro-2-{2-hydroxymethyl-3-[1-methyl-6-oxo-5-(5-trifluoromethyl-pyrazin-2-ylamino)-1,6-dihydro-pyridazin-3-yl]-phenyl}-2H-phthalazin-1-one.

The application provides a method for treating an inflammatory and/orautoimmune condition comprising administering to a patient in needthereof a therapeutically effective amount of the Btk inhibitor compoundof Formula I′.

The application provides a method for treating arthritis comprisingadministering to a patient in need thereof a therapeutically effectiveamount of the Btk inhibitor compound of Formula I′.

The application provides a method for treating asthma comprisingadministering to a patient in need thereof a therapeutically effectiveamount of the Btk inhibitor compound of Formula I′.

The application provides a method of inhibiting B-cell proliferationcomprising administering to a patient in need thereof a therapeuticallyeffective amount of the Btk inhibitor compound of Formula I′.

The application provides a method for inhibiting Btk activity comprisingadministering the Btk inhibitor compound of any one of Formula I′,wherein the Btk inhibitor compound exhibits an IC₅₀ of 50 micromolar orless in an in vitro biochemical assay of Btk activity.

In one variation of the above method, the Btk inhibitor compoundexhibits an IC₅₀ of 100 nanomolar or less in an in vitro biochemicalassay of Btk activity.

In another variation of the above method, the compound exhibits an IC₅₀of 10 nanomolar or less in an in vitro biochemical assay of Btkactivity.

The application provides a method for treating an inflammatory conditioncomprising co-administering to a patient in need thereof atherapeutically effective amount of an anti-inflammatory compound incombination with the Btk inhibitor compound of Formula I′.

The application provides a method for treating arthritis comprisingco-administering to a patient in need thereof a therapeuticallyeffective amount of an anti-inflammatory compound in combination withthe Btk inhibitor compound of Formula I′.

The application provides a method for treating a lymphoma or a BCR-ABL1⁺leukemia cells by administering to a patient in need thereof atherapeutically effective amount of the Btk inhibitor compound ofFormula I′.

The application provides a pharmaceutical composition comprising the Btkinhibitor compound of Formula I′, admixed with at least onepharmaceutically acceptable carrier, excipient or diluent.

The application provides a use of the compound of formula I′ in themanufacture of a medicament for the treatment of an inflammatorydisorder.

The application provides a use of the compound of formula I′ in themanufacture of a medicament for the treatment of an autoimmune disorder.

The application provides a compound, method, or composition as describedherein.

Compounds

Examples of representative compounds encompassed by the presentinvention and within the scope of the invention are provided in thefollowing Table. These examples and preparations which follow areprovided to enable those skilled in the art to more clearly understandand to practice the present invention. They should not be considered aslimiting the scope of the invention, but merely as being illustrativeand representative thereof.

In general, the nomenclature used in this Application is based onAUTONOMTM v.4.0, a Beilstein Institute computerized system for thegeneration of IUPAC systematic nomenclature. If there is a discrepancybetween a depicted structure and a name given that structure, thedepicted structure is to be accorded more weight. In addition, if thestereochemistry of a structure or a portion of a structure is notindicated with, for example, bold or dashed lines, the structure orportion of the structure is to be interpreted as encompassing allstereoisomers of it.

TABLE I depicts examples of pyridazinone compounds according to genericFormula I:

TABLE I Compound Nomenclature Structure I-1 6-tert-Butyl-2-(3-{5-[5-(1-ethylamino-1- methyl-ethyl)-pyridin-2- ylamino]-1-methyl-6-oxo-1,6-dihydro- pyridazin-3-yl}-2- hydroxymethyl-phenyl)-8-fluoro-2H-phthalazin- 1-one

I-2 6-tert-Butyl-8-fluoro-2- (2-hydroxymethyl-3-{1- methyl-5-[5-(morpholine-4- carbonyl)-pyridin-2- ylamino]-6-oxo-1,6-dihydro-pyridazin-3- yl}-phenyl)-2H- phthalazin-1-one

I-3 6-tert-Butyl-8-fluoro-2- {2-hydroxymethyl-3-[5- (5-methanesulfonyl-pyridin-2-ylamino)-1- methyl-6-oxo-1,6- dihydro-pyridazin-3-yl]-phenyl}-2H-phthalazin- 1-one

I-4 6-tert-Butyl-8-fluoro-2- (2-hydroxymethyl-3-{5-[5-(3-methoxy-azetidin- 1-ylmethyl)-pyridin-2- ylamino]-1-methyl-6-oxo-1,6-dihydro- pyridazin-3-yl}- phenyl)-2H-phthalazin- 1-one

I-5 6-tert-Butyl-8-fluoro-2- (2-hydroxymethyl-3-{1-methyl-5-[5-(8-methyl- 3,8-diaza- bicyclo[3.2.1]oct-3-ylmethyl)-pyridin-2- ylamino]-6-oxo-1,6- dihydro-pyridazin-3-yl}-phenyl)-2H- phthalazin-1-one

I-6 6-tert-Butyl-2-(3-{5-[5- (2-dimethylamino-1,1- dimethyl-ethoxy)-pyridin-2-ylamino]-1- methyl-6-oxo-1,6- dihydro-pyridazin-3-yl}-2-hydroxymethyl- phenyl)-8-fluoro-2H- phthalazin-1-one

I-7 2-{3-[5-(5-Azetidin-1- ylmethyl-pyridin-2- ylamino)-1-methyl-6-oxo-1,6-dihydro- pyridazin-3-yl]-2- hydroxymethyl-phenyl}-6-tert-butyl-8- fluoro-2H-phthalazin-1- one

I-8 6-tert-Butyl-2-{3-[5-(5- dimethylaminomethyl- pyridin-2-ylamino)-1-methy-l-6-oxo-1,6- dihydro-pyridazin-3-yl]- 2-hydroxymethyl-phenyl}-8-fluoro-2H- phthalazin-1-one

I-9 6-tert-Butyl-2-(3-{5- [(1R,5S)-5-(3,8-diaza-bicyclo[3.2.1]oct-8-yl)- pyridin-2-ylamino]-1- methyl-6-oxo-1,6-dihydro-pyridazin-3- yl}-2-hydroxymethyl- phenyl)-8-fluoro-2H-phthalazin-1-one

I-10 6-{6-[3-(6-tert-Butyl-8- fluoro-1-oxo-1H- phthalazin-2-yl)-2-hydroxymethyl-phenyl]- 2-methyl-3-oxo-2,3- dihydro-pyridazin-4-ylamino}-N,N- dimethyl-nicotinamide

I-11 6-tert-Butyl-8-fluoro-2- {2-hydroxymethyl-3-[1- methyl-6-oxo-5-(5-trifluoromethyl-pyrazin- 2-ylamino)-1,6-dihydro- pyridazin-3-yl]-phenyl}-2H-phthalazin- 1-one

I-12 6-tert-Butyl-8-fluoro-2- (3-{5-[5-(2-hydroxy- 1,1-dimethyl-ethoxy)-pyridin-2-ylamino]-1- methyl-6-oxo-1,6- dihydro-pyridazin-3-yl}-2-hydroxymethyl- phenyl)-2H-phthalazin- 1-one

I-13 2-(3-{5-[5-(2-Azetidin- 1-yl-1,1-dimethyl- ethoxy)-pyridin-2-ylamino]-1-methyl-6- oxo-1,6-dihydro- pyridazin-3-yl}-2-hydroxymethyl-phenyl)- 6-tert-butyl-8-fluoro- 2H-phthalazin-1-one

I-14 6-tert-Butyl-8-fluoro-2- (2-hydroxymethyl-3-{5- [5-(2-hydroxy-2-methyl-propoxy)- pyridin-2-ylamino]-1- methyl-6-oxo-1,6-dihydro-pyridazin-3- yl}-phenyl)-2H- phthalazin-1-one

I-15 2-[8-Fluoro-2-(2- hydroxymethyl-3-{1- methyl-5-[5- (morpholine-4-carbonyl)-pyridin-2- ylamino]-6-oxo-1,6- dihydro-pyridazin-3-yl}-phenyl)-1-oxo-1,2- dihydro-isoquinolin-6- yl]-2-methyl-propionitrile

I-16 6-tert-Butyl-8-fluoro-2- (3-{5-[5-((S)-2- hydroxy-3-methoxy-propoxy)-pyridin-2- ylamino]-1-methyl-6- oxo-1,6-dihydro-pyridazin-3-yl}-2- hydroxymethyl-phenyl)- 2H-phthalazin-1-one

I-17 6-tert-Butyl-8-fluoro-2- (3-{5-[5-((R)-2- hydroxy-3-methoxy-propoxy)-pyridin-2- ylamino]-1-methyl-6- oxo-1,6-dihydro-pyridazin-3-yl}-2- hydroxymethyl-phenyl)- 2H-phthalazin-1-one

I-18 6-tert-Butyl-8-fluoro-2- (2-hydroxymethyl-3-{1- methyl-5-[5-((S)-1-methyl-pyrrolidin-2-yl)- pyridin-2-ylamino]-6- oxo-1,6-dihydro-pyridazin-3-yl}- phenyl)-2H-phthalazin- 1-one

I-19 6-tert-Butyl-8-fluoro-2- (2-hydroxymethyl-3-{1- methyl-5-[5-((R)-1-methyl-pyrrolidin-2-yl)- pyridin-2-ylamino]-6- oxo-1,6-dihydro-pyridazin-3-yl}- phenyl)-2H-phthalazin- 1-one

I-20 6-{6-[3-(6-tert-Butyl-8- fluoro-1-oxo-1H- phthalazin-2-yl)-2-hydroxymethyl-phenyl]- 2-methyl-3-oxo-2,3- dihydro-pyridazin-4-ylamino}-N,N- dimethyl-nicotinamide

I-21 6-tert-Butyl-8-fluoro-2- (2-hydroxymethyl-3-{5- [5-(4-hydroxy-4-methyl-piperidine-1- carbonyl)-pyridin-2- ylamino]-1-methyl-6-oxo-1,6-dihydro- pyridazin-3-yl}- phenyl)-2H-phthalazin- 1-one

I-22 6-tert-Butyl-8-fluoro-2- (2-hydroxymethyl-3-{1-methyl-5-[5-(6-methyl- 2,6-diaza- spiro[3.3]hept-2-yl)-pyridin-2-ylamino]-6- oxo-1,6-dihydro- pyridazin-3-yl}-phenyl)-2H-phthalazin- 1-one

I-23 6-tert-Butyl-2-{3-[5-(5- ethanesulfonyl-pyridin-2-ylamino)-1-methyl-6- oxo-1,6-dihydro- pyridazin-3-yl]-2-hydroxymethyl- phenyl}-8-fluoro-2H- phthalazin-1-one

I-24 6-tert-Butyl-8-fluoro-2- (2-hydroxymethyl-3-{1- methyl-6-oxo-5-[5-(propane-2-sulfonyl)- pyridin-2-ylamino]-1,6- dihydro-pyridazin-3-yl}-phenyl)-2H- phthalazin-1-one

I-25 6-tert-Butyl-8-fluoro-2- (3-{5-[5-(2-hydroxy-ethylsulfanyl)-pyridin- 2-ylamino]-1-methyl-6- oxo-1,6-dihydro-pyridazin-3-yl}-2- hydroxymethyl-phenyl)- 2H-phthalazin-1-one

I-26 6-tert-Butyl-8-fluoro-2- (3-{5-[5-(2-hydroxy-ethanesulfonyl)-pyridin- 2-ylamino]-1-methyl-6- oxo-1,6-dihydro-pyridazin-3-yl}-2- hydroxymethyl-phenyl)- 2H-phthalazin-1-one

I-27 6-tert-Butyl-8-fluoro-2- (2-hydroxymethyl-3-{5- [5-(4-isopropyl-piperazin-1-yl)-pyridin- 2-ylamino]-1-methyl-6- oxo-1,6-dihydro-pyridazin-3-yl}- phenyl)-2H-phthalazin- 1-one

I-28 6-tert-Butyl-8-fluoro-2- (2-hydroxymethyl-3-{1-methyl-5-[5-(1-methyl- pyrrolidin-3-yl)-pyridin- 2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3- yl}-phenyl)-2H- phthalazin-1-one

I-29 6-tert-Butyl-8-fluoro-2- {2-hydroxymethyl-3-[5- (1′-isopropyl-1′,2′,3′,4′,5′,6′- hexahydro- [3,4′]bipyridinyl-6- ylamino)-1-methyl-6-oxo-1,6-dihydro- pyridazin-3-yl]- phenyl}-2H-phthalazin- 1-one

I-30 6-tert-Butyl-2-{3-[5- (1′-ethyl-1′,2′,3′,4′,5′,6′- hexahydro-[3,4′]bipyridinyl-6- ylamino)-1-methyl-6- oxo-1,6-dihydro-pyridazin-3-yl]-2- hydroxymethyl- phenyl}-8-fluoro-2H- phthalazin-1-one

I-31 6-tert-Butyl-2-{3-[5- (1,5-dimethyl-1H- pyrazol-3-ylamino)-1-methyl-6-oxo-1,6- dihydro-pyridazin-3-yl]- 2-hydroxymethyl-phenyl}-8-fluoro-2H- phthalazin-1-one

I-32 6-tert-Butyl-8-fluoro-2- (2-hydroxymethyl-3-{1- methyl-5-[5-((S)-1-methyl-pyrrolidin-3-yl)- pyridin-2-ylamino]-6- oxo-1,6-dihydro-pyridazin-3-yl}- phenyl)-2H-phthalazin- 1-one

I-33 6-tert-Butyl-8-fluoro-2- (2-hydroxymethyl-3-{1- methyl-5-[5-((R)-1-methyl-pyrrolidin-3-yl)- pyridin-2-ylamino]-6- oxo-1,6-dihydro-pyridazin-3-yl}- phenyl)-2H-phthalazin- 1-one

I-34 6-tert-Butyl-8-fluoro-2- {2-hydroxymethyl-3-[1- methyl-5-(4-methyl-3,4,5,6-tetrahydro-2H- [1,2′]bipyrazinyl-5′- ylamino)-6-oxo-1,6-dihydro-pyridazin-3-yl]- phenyl}-2H-phthalazin- 1-one

I-35 6-tert-Butyl-2-{3-[5-(5- cyclobutylaminomethyl-pyrazin-2-ylamino)-1- methyl-6-oxo-1,6- dihydro-pyridazin-3-yl]-2-hydroxymethyl- phenyl}-8-fluoro-2H- phthalazin-1-one

I-36 6-tert-Butyl-2-(3-{5-[5- (2-dimethylamino- ethoxy)-pyrazin-2-ylamino]-1-methyl-6- oxo-1,6-dihydro- pyridazin-3-yl}-2-hydroxymethyl-phenyl)- 8-fluoro-2H-phthalazin- 1-one

I-37 6-tert-Butyl-8-fluoro-2- (2-hydroxymethyl-3-{1-methyl-5-[5-(4-methyl- piperazin-1-ylmethyl)- pyrazin-2-ylamino]-6-oxo-1,6-dihydro- pyridazin-3-yl}- phenyl)-2H-phthalazin- 1-one

I-38 6-tert-Butyl-2-(3-{5-[5- (2-dimethylamino-1,1- dimethyl-ethoxy)-pyrazin-2-ylamino]-1- methyl-6-oxo-1,6- dihydro-pyridazin-3-yl}-2-hydroxymethyl- phenyl)-8-fluoro-2H- phthalazin-1-one

I-39 6-tert-Butyl-2-(3-{5-[6- (2-dimethylamino-1,1- dimethyl-ethoxy)-pyridazin-3-ylamino]-1- methyl-6-oxo-1,6- dihydro-pyridazin-3-yl}-2-hydroxymethyl- phenyl)-8-fluoro-2H- phthalazin-1-one

I-40 6-tert-Butyl-8-fluoro-2- (2-hydroxymethyl-3-{1-methyl-5-[6-(1-methyl- piperidin-4-yl)- pyridazin-3-ylamino]-6-oxo-1,6-dihydro- pyridazin-3-yl}- phenyl)-2H-phthalazin- 1-one

I-41 6-tert-Butyl-8-fluoro-2- (2-hydroxymethyl-3-{1-methyl-5-[5-(4-methyl- piperazin-1-ylmethyl)- pyridin-2-ylamino]-6-oxo-1,6-dihydro- pyridazin-3-yl}- phenyl)-2H-phthalazin- 1-one

I-42 6-tert-Butyl-8-fluoro-2- [2-hydroxymethyl-3-(5- {5-[(2-methoxy-ethylamino)-methyl]- pyridin-2-ylamino}-1- methyl-6-oxo-1,6-dihydro-pyridazin-3-yl)- phenyl]-2H-phthalazin- 1-one

I-43 6-tert-Butyl-8-fluoro-2- (2-hydroxymethyl-3-{1-methyl-5-[5-((1S,4S)-5- methyl-2,5-diaza- bicyclo[2.2.1]hept-2-ylmethyl)-pyridin-2- ylamino]-6-oxo-1,6- dihydro-pyridazin-3-yl}-phenyl)-2H- phthalazin-1-one

I-44 6-tert-Butyl-8-fluoro-2- {2-hydroxymethyl-3-[5-(5-{[(2-methoxy-ethyl)- methyl-amino]- methyl}-pyridin-2-ylamino)-1-methyl-6- oxo-1,6-dihydro- pyridazin-3-yl]-phenyl}-2H-phthalazin- 1-one

I-45 6-tert-Butyl-8-fluoro-2- (2-hydroxymethyl-3-{1-methyl-5-[6-(4-methyl- piperazin-1-yl)- pyridazin-3-ylamino]-6-oxo-1,6-dihydro- pyridazin-3-yl}- phenyl)-2H-phthalazin- 1-one

I-46 6-tert-Butyl-8-fluoro-2- (2-hydroxymethyl-3-{1-methyl-5-[6-((1S,4S)-5- methyl-2,5-diaza- bicyclo[2.2.1]hept-2-yl)-pyridazin-3- ylamino]-6-oxo-1,6- dihydro-pyridazin-3-yl}-phenyl)-2H- phthalazin-1-one

I-47 2-(3-{5-[5-(Azetidine- 1-carbonyl)-pyridin-2- ylamino]-1-methyl-6-oxo-1,6-dihydro- pyridazin-3-yl}-2- hydroxymethyl-phenyl)-6-tert-butyl-8-fluoro- 2H-phthalazin-1-one

I-48 6-tert-Butyl-2-(3-{5-[5- (1,1-dioxo-1λ6- thiomorpholine-4-carbonyl)-pyridin-2- ylamino]-1-methyl-6- oxo-1,6-dihydro-pyridazin-3-yl}-2- hydroxymethyl-phenyl)- 8-fluoro-2H-phthalazin- 1-one

I-49 6-tert-Butyl-8-fluoro-2- (2-hydroxymethyl-3-{1-methyl-5-[5-(2-oxa-6- aza-spiro[3.3]heptane-6- carbonyl)-pyridin-2-ylamino]-6-oxo-1,6- dihydro-pyridazin-3- yl}-phenyl)-2H-phthalazin-1-one

I-50 6-tert-Butyl-8-fluoro-2- (2-hydroxymethyl-3-{1-methyl-5-[5-(6-methyl- 2,6-diaza- spiro[3.3]heptane-2-carbonyl)-pyridin-2- ylamino]-6-oxo-1,6- dihydro-pyridazin-3-yl}-phenyl)-2H- phthalazin-1-one

I-51 6-{6-[3-(6-tert-Butyl-8- fluoro-1-oxo-1H- phthalazin-2-yl)-2-hydroxymethyl-phenyl]- 2-methyl-3-oxo-2,3- dihydro-pyridazin-4-ylamino}-N-(2- dimethylamino-ethyl)- nicotinamide

I-52 6-{6-[3-(6-tert-Butyl-8- fluoro-1-oxo-1H- phthalazin-2-yl)-2-hydroxymethyl-phenyl]- 2-methyl-3-oxo-2,3- dihydro-pyridazin-4-ylamino}-N-(2- hydroxy-ethyl)-N- methyl-nicotinamide

I-53 1-(6-{6-[3-(6-tert- Butyl-8-fluoro-1-oxo- 1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]- 2-methyl-3-oxo-2,3- dihydro-pyridazin-4-ylamino}-pyridine-3- carbonyl)-azetidine-3- carbonitrile

I-54 6-tert-Butyl-8-fluoro-2- (2-hydroxymethyl-3-{5- [5-(3-hydroxy-pyrrolidine-1-carbonyl)- pyridin-2-ylamino]-1- methyl-6-oxo-1,6-dihydro-pyridazin-3- yl}-phenyl)-2H- phthalazin-1-one

I-55 6-tert-Butyl-8-fluoro-2- (2-hydroxymethyl-3-{5- [5-(4-hydroxy-piperidine-1-carbonyl)- pyridin-2-ylamino]-1- methyl-6-oxo-1,6-dihydro-pyridazin-3- yl}-phenyl)-2H- phthalazin-1-one

I-56 6-tert-Butyl-8-fluoro-2- (2-hydroxymethyl-3-{1-methyl-5-[5-(4-methyl- piperazin-1-yl)-pyridin- 2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3- yl}-phenyl)-2H- phthalazin-1-one

I-57 6-tert-Butyl-2-(3-{5-[5- ((S)-1,2-dihydroxy- ethyl)-pyrazin-2-ylamino]-1-methyl-6- oxo-1,6-dihydro- pyridazin-3-yl}-2-hydroxymethyl-phenyl)- 8-fluoro-2H-phthalazin- 1-one

I-58 2-{3-[5-(5-Azetidin-1- ylmethyl-1-methyl-1H- pyrazol-3-ylamino)-1-methyl-6-oxo-1,6- dihydro-pyridazin-3-yl]- 2-hydroxymethyl-phenyl}-6-tert-butyl-8- fluoro-2H-phthalazin-1- one

I-59 6-tert-Butyl-8-fluoro-2- {2-hydroxymethyl-3-[1- methyl-5-(5-methyl-4,5,6,7-tetrahydro- pyrazolo[1,5-a]pyrazin- 2-ylamino)-6-oxo-1,6-dihydro-pyridazin-3-yl]- phenyl}-2H-phthalazin- 1-one

I-60 6-tert-Butyl-8-fluoro-2- {2-hydroxymethyl-3-[1-methyl-5-(5-oxetan-3- yl-4,5,6,7-tetrahydro- pyrazolo[1,5-a]pyrazin-2-ylamino)-6-oxo-1,6- dihydro-pyridazin-3-yl]- phenyl}-2H-phthalazin-1-one

I-61 6-tert-Butyl-8-fluoro-2- {3-[5-(1′,2′,3′,4′,5′,6′- hexahydro-[3,4′]bipyridinyl-6- ylamino)-1-methyl-6- oxo-1,6-dihydro-pyridazin-3-yl]-2- hydroxymethyl- phenyl}-2H-phthalazin- 1-one

I-62 6-tert-Butyl-8-fluoro-2- {2-hydroxymethyl-3-[5-(1′-methanesulfonyl- 1′,2′,3′,4′,5′,6′- hexahydro- [3,4′]bipyridinyl-6-ylamino)-1-methyl-6- oxo-1,6-dihydro- pyridazin-3-yl]-phenyl}-2H-phthalazin- 1-one

I-63 2-{3-[5-(1′-Acetyl- 1′,2′,3′,4′,5′,6′- hexahydro-[3,4′]bipyridinyl-6- ylamino)-1-methyl-6- oxo-1,6-dihydro-pyridazin-3-yl]-2- hydroxymethyl- phenyl}-6-tert-butyl-8-fluoro-2H-phthalazin-1- one

I-64 6-tert-Butyl-8-fluoro-2- {2-hydroxymethyl-3-[5-(4-hydroxy-4-methyl- 3,4,5,6-tetrahydro-2H- [1,3′]bipyridinyl-6′-ylamino)-1-methyl-6- oxo-1,6-dihydro- pyridazin-3-yl]-phenyl}-2H-phthalazin- 1-one

I-65 6-tert-Butyl-8-fluoro-2- {2-hydroxymethyl-3-[5- (4-hydroxy-3,4,5,6-tetrahydro-2H- [1,3′]bipyridinyl-6′- ylamino)-1-methyl-6-oxo-1,6-dihydro- pyridazin-3-yl]- phenyl}-2H-phthalazin- 1-one

I-66 6-tert-Butyl-8-fluoro-2- (2-hydroxymethyl-3-{1-methyl-5-[5-((1R,5S)-3- methyl-3,8-diaza- bicyclo[3.2.1]oct-8-yl)-pyridin-2-ylamino]-6- oxo-1,6-dihydro- pyridazin-3-yl}-phenyl)-2H-phthalazin- 1-one

I-67 6-tert-Butyl-8-fluoro-2- {2-hydroxymethyl-3-[1-methyl-5-(1′-methyl- 1′,2′,3′,4′,5′,6′- hexahydro- [3,4′]bipyridinyl-6-ylamino)-6-oxo-1,6- dihydro-pyridazin-3-yl]- phenyl}-2H-phthalazin-1-one

I-68 6-tert-Butyl-2-(3-{5-[1- ((R)-2,3-dihydroxy- propyl)-1H-pyrazol-3-ylamino]-1-methyl-6- oxo-1,6-dihydro- pyridazin-3-yl}-2-hydroxymethyl-phenyl)- 8-fluoro-2H-phthalazin- 1-one

I-69 6-tert-Butyl-2-(3-{5-[5- (4-ethyl-piperazin-1-yl)-pyridin-2-ylamino]-1- methyl-6-oxo-1,6- dihydro-pyridazin-3-yl}-2-hydroxymethyl- phenyl)-8-fluoro-2H- phthalazin-1-one

I-70 6-tert-Butyl-8-fluoro-2- (2-hydroxymethyl-3-{5- [1-(2-hydroxy-2-methyl-propyl)-1H- pyrazol-3-ylamino]-1- methyl-6-oxo-1,6-dihydro-pyridazin-3- yl}-phenyl)-2H- phthalazin-1-one

I-71 2-(8-Fluoro-2-{2- hydroxymethyl-3-[1- methyl-5-(1′-methyl-1′,2′,3′,4′,5′,6′- hexahydro- [3,4′]bipyridinyl-6- ylamino)-6-oxo-1,6-dihydro-pyridazin-3-yl]- phenyl}-1-oxo-1,2- dihydro-isoquinolin-6-yl)-2-methyl- propionitrile

I-72 2-(2-{3-[5-(5-Azetidin- 1-ylmethyl-1-methyl- 1H-pyrazol-3-ylamino)-1-methyl-6-oxo-1,6- dihydro-pyridazin-3-yl]- 2-hydroxymethyl-phenyl}-8-fluoro-1-oxo- 1,2-dihydro- isoquinolin-6-yl)-2-methyl-propionitrile

I-73 2-[2-(3-{5-[5-(2- Azetidin-1-yl-1,1- dimethyl-ethoxy)-pyridin-2-ylamino]-1- methyl-6-oxo-1,6- dihydro-pyridazin-3-yl}-2-hydroxymethyl- phenyl)-8-fluoro-1-oxo- 1,2-dihydro-isoquinolin-6-yl]-2- methyl-propionitrile

I-74 2-(8-Fluoro-2-{2- hydroxymethyl-3-[1- methyl-5-(5-methyl-4,5,6,7-tetrahydro- pyrazolo[1,5-a]pyrazin- 2-ylamino)-6-oxo-1,6-dihydro-pyridazin-3-yl]- phenyl}-1-oxo-1,2- dihydro-isoquinolin-6-yl)-2-methyl- propionitrile

I-75 6-(6-{3-[6-(Cyano- dimethyl-methyl)-8- fluoro-1-oxo-1H-isoquinolin-2-yl]-2- hydroxymethyl- phenyl}-2-methyl-3- oxo-2,3-dihydro-pyridazin-4-ylamino)- N,N-dimethyl- nicotinamide

I-76 2-[8-Fluoro-2-(2- hydroxymethyl-3-{1- methyl-5-[5-((S)-1-methyl-pyrrolidin-2-yl)- pyridin-2-ylamino]-6- oxo-1,6-dihydro-pyridazin-3-yl}- phenyl)-1-oxo-1,2- dihydro-isoquinolin-6- yl]-2-methyl-propionitrile

I-77 2-[8-Fluoro-2-(2- hydroxymethyl-3-{1- methyl-5-[5-((S)-1-methyl-pyrrolidin-3-yl)- pyridin-2-ylamino]-6- oxo-1,6-dihydro-pyridazin-3-yl}- phenyl)-1-oxo-1,2- dihydro-isoquinolin-6- yl]-2-methyl-propionitrile

I-78 2-[2-(3-{5-[5-(2- Azetidin-1-yl-1,1- dimethyl-ethoxy)-pyridin-2-ylamino]-1- methyl-6-oxo-1,6- dihydro-pyridazin-3-yl}-2-hydroxymethyl- phenyl)-8-fluoro-1-oxo- 1,2,3,4-tetrahydro-isoquinolin-6-yl]-2- methyl-propionitrile

I-79 2-(8-Fluoro-2-{2- hydroxymethyl-3-[1- methyl-5-(5-oxetan-3-yl-4,5,6,7-tetrahydro- pyrazolo[1,5-a]pyrazin- 2-ylamino)-6-oxo-1,6-dihydro-pyridazin-3-yl]- phenyl}-1-oxo-1,2- dihydro-isoquinolin-6-yl)-2-methyl- propionitrile

I-80 6-tert-Butyl-8-fluoro-2- {2-hydroxymethyl-3-[1-methyl-5-(1′-oxetan-3- yl-1′,2′,3′,4′,5′,6′- hexahydro-[3,4′]bipyridinyl-6- ylamino)-6-oxo-1,6- dihydro-pyridazin-3-yl]-phenyl}-2H-phthalazin- 1-one

I-81 2-(8-Fluoro-2-{2- hydroxymethyl-3-[1- methyl-5-(1′-oxetan-3-yl-1′,2′,3′,4′,5′,6′- hexahydro- [3,4′]bipyridinyl-6-ylamino)-6-oxo-1,6- dihydro-pyridazin-3-yl]- phenyl}-1-oxo-1,2-dihydro-isoquinolin-6- yl)-2-methyl- propionitrile

I-82 6-tert-Butyl-2-{3-[5-(5- ethyl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazin- 2-ylamino)-1-methyl-6- oxo-1,6-dihydro-pyridazin-3-yl]-2- hydroxymethyl- phenyl}-8-fluoro-2H- phthalazin-1-one

I-83 2-(2-{3-[5-(5-Ethyl- 4,5,6,7-tetrahydro- pyrazolo[1,5-a]pyrazin-2-ylamino)-1-methyl-6- oxo-1,6-dihydro- pyridazin-3-yl]-2-hydroxymethyl- phenyl}-8-fluoro-1-oxo- 1,2-dihydro- isoquinolin-6-yl)-2-methyl-propionitrile

I-84 6-tert-Butyl-2-[3-(5- {5-[(1S,4S)-1-(2,5- diaza-bicyclo[2.2.1]hept-2- yl)methyl]-pyridin-2- ylamino}-1-methyl-6-oxo-1,6-dihydro- pyridazin-3-yl)-2- hydroxymethyl- phenyl]-8-fluoro-2H-phthalazin-1-one

I-85 6-tert-Butyl-8-fluoro- 2-(2-hydroxymethyl-3- {5-[5-(4-hydroxy-4-methyl-piperidin-1- ylmethyl)-pyridin-2- ylamino]-1-methyl-6-oxo-1,6-dihydro- pyridazin-3-yl}- phenyl)-2H-phthalazin- 1-one

I-86 4-(6-{6-[3-(6-tert- Butyl-8-fluoro-1-oxo- 1H-phthalazin-2-yl)-2-hydroxymethyl- phenyl]-2-methyl-3- oxo-2,3-dihydro-pyridazin-4-ylamino}- pyridin-3-yl)- piperazine-1-carboxylic acid ethylester

I-87 8-Fluoro-6-(2-fluoro- 1,1-dimethyl-ethyl)-2- (2-hydroxymethyl-3-{1-methyl-5-[5- (morpholine-4- carbonyl)-pyridin-2- ylamino]-6-oxo-1,6-dihydro-pyridazin-3- yl}-phenyl)-2H- isoquinolin-1-one

I-88 6-tert-Butyl-8-fluoro- 2-(2-hydroxymethyl-3- {1-methyl-5-[5-((1S,4S)-5-methyl-2,5- diaza- bicyclo[2.2.1]hept-2-yl)-pyrazin-2-ylamino]- 6-oxo-1,6-dihydro- pyridazin-3-yl}-phenyl)-2H-phthalazin- 1-one

I-89 2-[8-Fluoro-2-(2- hydroxymethyl-3-{1- methyl-5-[5-((R)-1-methyl-pyrrolidin-3- yl)-pyridin-2-ylamino]- 6-oxo-1,6-dihydro-pyridazin-3-yl}- phenyl)-1-oxo-1,2- dihydro-isoquinolin-6- yl]-2-methyl-propionitrile

I-90 6-tert-Butyl-8-fluoro- 2-(2-hydroxymethyl-3- {1-methyl-6-oxo-5-[1′-(2,2,2-trifluoro-ethyl)- 1′,2′,3′,4′,5′,6′- hexahydro-[3,4′]bipyridinyl-6- ylamino]-1,6-dihydro- pyridazin-3-yl}-phenyl)-2H-phthalazin- 1-one

SYNTHESIS General Synthetic Schemes

This application is related to U.S. patent application Ser. No.12/711,312, filed on Feb. 24, 2010, the disclosure of which isincorporated herein by reference in its entirety.

Wherein Y⁴ can be Y^(4a), Y^(4b), Y^(4c), Y^(4c), or Y^(4a) can be H orhalogen; Y^(4b) can be lower alkyl, optionally substituted with one ormore substituents selected from the group consisting of lower haloalkyl,halogen, hydroxy, amino, cyano, and lower alkoxy; Y^(4c) can be lowercycloalkyl, optionally substituted with one or more substituentsselected from the group consisting of lower alkyl, lower haloalkyl,halogen, hydroxy, amino, cyano, and lower alkoxy; and Y^(4d) can beamino, optionally substituted with one or more lower alkyl, alkoxy loweralkyl, or hydroxy lower alkyl.

Wherein R can be H, -R¹, R¹-R²-R³, -R¹-R³, or -R²-R³; R¹ can be aryl,heteroaryl, bicylic heteroaryl, cycloalkyl, or heterocycloalkyl, each ofwhich can be optionally substituted with one or more lower alkyl,hydroxy, hydroxy lower alkyl, lower alkoxy, halo, nitro, amino, amido,cyano, oxo, or lower haloalkyl; R² can be —C(═O), —C(═O)O,—C(═O)NR^(2′), —NHC(═O)O, —C(R^(2′))₂, —O, —S, —C(═NH)NR^(2′), or—S(═O)₂; each R^(2′) can be independently H or lower alkyl; R³ can be Hor R⁴; R⁴ can be lower alkyl, lower haloalkyl, lower alkoxy, amino,lower alkyl amino, cycloalkyl amino, lower dialkyl amino, aryl,arylalkyl, alkylaryl, heteroaryl, alkyl heteroaryl, heteroaryl alkyl,cycloalkyl, alkyl cycloalkyl, cycloalkyl alkyl, heterocycloalkyl, alkylheterocycloalkyl, heterocycloalkyl alkyl, bicyclic cycloalkyl, bicyclicheterocycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, or bicyclicspiroheterocycloalkyl each of which can be optionally substituted withone or more lower alkyl, halo, lower alkyl amino, lower dialkyl amino,hydroxy, hydroxy lower alkyl, lower alkoxy, lower alkanoyl, halo, nitro,amino, amido, acyl, cyano, oxo, sulfonyl, lower alkyl sulfonyl,guanidino, hydroxyl amino, carboxy, carbamoyl, carbamate, halo loweralkoxy, heterocycloalkyl, or halo lower alkyl, wherein two lower alkylgroups may together form a ring.

Wherein R can be -R²-R³ or -R³; R² can be —C(═O), —C(═O)O,—C(═O)NR^(2′), —NHC(═O)O, —C(R^(2′))₂, —O, —S, —C(═NH)NR^(2′), or—S(═O)₂; each R^(2′) can be independently H or lower alkyl; R³ can be Hor R⁴; R⁴ can be lower alkyl, lower haloalkyl, lower alkoxy, amino,lower alkyl amino, cycloalkyl amino, lower dialkyl amino, aryl,arylalkyl, alkylaryl, heteroaryl, alkyl heteroaryl, heteroaryl alkyl,cycloalkyl, alkyl cycloalkyl, cycloalkyl alkyl, heterocycloalkyl, alkylheterocycloalkyl, heterocycloalkyl alkyl, bicyclic cycloalkyl, bicyclicheterocycloalkyl, spirocycloalkyl, spiroheterocycloalkyl or bicyclicspiroheterocycloalkyl, each of which can be optionally substituted withone or more lower alkyl, halo, lower alkyl amino, lower dialkyl amino,hydroxy, hydroxy lower alkyl, lower alkoxy, lower alkanoyl, halo, nitro,amino, amido, acyl, cyano, oxo, sulfonyl, lower alkyl sulfonyl,guanidino, hydroxyl amino, carboxy, carbamoyl, carbamate, halo loweralkoxy, heterocycloalkyl, or halo lower alkyl, wherein two lower alkylgroups may together form a ring.

Wherein each R^(2′) can be independently H or lower alkyl; Y⁴ can beY^(4a), Y^(bb), Y^(4c), or Y^(4d); Y^(4a) can be H or halogen; Y^(4b)can be lower alkyl, optionally substituted with one or more substituentsselected from the group consisting of lower haloalkyl, halogen, hydroxy,amino, cyano, and lower alkoxy; Y^(4c) can be lower cycloalkyl,optionally substituted with one or more substituents selected from thegroup consisting of lower alkyl, lower haloalkyl, halogen, hydroxy,amino, cyano, and lower alkoxy; and Y^(4d) can be amino, optionallysubstituted with one or more lower alkyl, alkoxy lower alkyl, or hydroxylower alkyl.

Wherein each R^(2′) can be independently H or lower alkyl; Y⁴ can beY^(4a), Y^(4b), Y^(4c), or Y^(4d); Y^(4a) can be H or halogen; Y^(4b)can be lower alkyl, optionally substituted with one or more substituentsselected from the group consisting of lower haloalkyl, halogen, hydroxy,amino, cyano, and lower alkoxy; Y^(4c) can be lower cycloalkyl,optionally substituted with one or more substituents selected from thegroup consisting of lower alkyl, lower haloalkyl, halogen, hydroxy,amino, cyano, and lower alkoxy; and Y^(4d) can be amino, optionallysubstituted with one or more lower alkyl, alkoxy lower alkyl, or hydroxylower alkyl.

Pharmacological Activity

The pyridazinone derivatives described herein are kinase inhibitors, inparticular Btk inhibitors. These inhibitors can be useful for treatingone or more diseases responsive to kinase inhibition, including diseasesresponsive to Btk inhibition and/or inhibition of B-cell proliferation,in mammals. Without wishing to be bound to any particular theory, it isbelieved that the interaction of the compounds of the invention with Btkresults in the inhibition of Btk activity and thus in the pharmaceuticalutility of these compounds. Accordingly, the invention includes a methodof treating a mammal, for instance a human, having a disease responsiveto inhibition of Btk activity, and/or inhibiting B-cell proliferation,comprising administrating to the mammal having such a disease, aneffective amount of at least one chemical entity provided herein. Aneffective concentration may be ascertained experimentally, for exampleby assaying blood concentration of the compound, or theoretically, bycalculating bioavailability. Other kinases that may be affected inaddition to Btk include, but are not limited to, other tyrosine kinasesand serine/threonine kinases.

Kinases play notable roles in signaling pathways controlling fundamentalcellular processes such as proliferation, differentiation, and death(apoptosis). Abnormal kinase activity has been implicated in a widerange of diseases, including multiple cancers, autoimmune and/orinflammatory diseases, and acute inflammatory reactions. Themultifaceted role of kinases in key cell signaling pathways provides asignificant opportunity to identify novel drugs targeting kinases andsignaling pathways.

An embodiment includes a method of treating a patient having anautoimmune and/or inflammatory disease, or an acute inflammatoryreaction responsive to inhibition of Btk activity and/or B-cellproliferation.

Autoimmune and/or inflammatory diseases that can be affected usingcompounds and compositions according to the invention include, but arenot limited to: psoriasis, allergy, Crohn's disease, irritable bowelsyndrome, Sjogren's disease, tissue graft rejection, and hyperacuterejection of transplanted organs, asthma, systemic lupus erythematosus(and associated glomerulonephritis), dermatomyositis, multiplesclerosis, scleroderma, vasculitis (ANCA-associated and othervasculitides), autoimmune hemolytic and thrombocytopenic states,Goodpasture's syndrome (and associated glomerulonephritis and pulmonaryhemorrhage), atherosclerosis, rheumatoid arthritis, chronic Idiopathicthrombocytopenic purpura (ITP), Addison's disease, Parkinson's disease,Alzheimer's disease, diabetes, septic shock, and myasthenia gravis.

Included herein are methods of treatment in which at least one chemicalentity provided herein is administered in combination with ananti-inflammatory agent. Anti-inflammatory agents include but are notlimited to NSAIDs, non-specific and COX-2 specific cyclooxygenase enzymeinhibitors, gold compounds, corticosteroids, methotrexate, tumornecrosis factor receptor (TNF) receptors antagonists, immunosuppressantsand methotrexate.

Examples of NSAIDs include, but are not limited to, ibuprofen,flurbiprofen, naproxen and naproxen sodium, diclofenac, combinations ofdiclofenac sodium and misoprostol, sulindac, oxaprozin, diflunisal,piroxicam, indomethacin, etodolac, fenoprofen calcium, ketoprofen,sodium nabumetone, sulfasalazine, tolmetin sodium, andhydroxychloroquine. Examples of NSAIDs also include COX-2 specificinhibitors such as celecoxib, valdecoxib, lumiracoxib and/or etoricoxib.

In some embodiments, the anti-inflammatory agent is a salicylate.Salicylates include by are not limited to acetylsalicylic acid oraspirin, sodium salicylate, and choline and magnesium salicylates.

The anti-inflammatory agent may also be a corticosteroid. For example,the corticosteroid may be cortisone, dexamethasone, methylprednisolone,prednisolone, prednisolone sodium phosphate, or prednisone.

In additional embodiments the anti-inflammatory agent is a gold compoundsuch as gold sodium thiomalate or auranofin.

The invention also includes embodiments in which the anti-inflammatoryagent is a metabolic inhibitor such as a dihydrofolate reductaseinhibitor, such as methotrexate or a dihydroorotate dehydrogenaseinhibitor, such as leflunomide.

Other embodiments of the invention pertain to combinations in which atleast one anti-inflammatory compound is an anti-C5 monoclonal antibody(such as eculizumab or pexelizumab), a TNF antagonist, such asentanercept, or infliximab, which is an anti-TNF alpha monoclonalantibody.

Still other embodiments of the invention pertain to combinations inwhich at least one active agent is an immunosuppressant compound such asan immunosuppressant compound chosen from methotrexate, leflunomide,cyclosporine, tacrolimus, azathioprine, and mycophenolate mofetil.

B-cells and B-cell precursors expressing BTK have been implicated in thepathology of B-cell malignancies, including, but not limited to, B-celllymphoma, lymphoma (including Hodgkin's and non-Hodgkin's lymphoma),hairy cell lymphoma, multiple myeloma, chronic and acute myelogenousleukemia and chronic and acute lymphocytic leukemia.

BTK has been shown to be an inhibitor of the Fas/APO-1 (CD-95) deathinducing signaling complex (DISC) in B-lineage lymphoid cells. The fateof leukemia/lymphoma cells may reside in the balance between theopposing proapoptotic effects of caspases activated by DISC and anupstream anti-apoptotic regulatory mechanism involving BTK and/or itssubstrates (Vassilev et al., J. Biol. Chem. 1998, 274, 1646-1656).

It has also been discovered that BTK inhibitors are useful aschemosensitizing agents, and, thus, are useful in combination with otherchemotherapeutic drugs, in particular, drugs that induce apoptosis.Examples of other chemotherapeutic drugs that can be used in combinationwith chemosensitizing BTK inhibitors include topoisomerase I inhibitors(camptothecin or topotecan), topoisomerase II inhibitors (e.g.daunomycin and etoposide), alkylating agents (e.g. cyclophosphamide,melphalan and BCNU), tubulin directed agents (e.g. taxol andvinblastine), and biological agents (e.g. antibodies such as anti CD20antibody, IDEC 8, immunotoxins, and cytokines).

Btk activity has also be associated with some leukemias expressing thebcr-abl fusion gene resulting from translocation of parts of chromosome9 and 22. This abnormality is commonly observed in chronic myelogenousleukemia. Btk is constitutively phosphorylated by the bcr-abl kinasewhich initiates downstream survival signals which circumvents apoptosisin bcr-abl cells. (N. Feldhahn et al. J. Exp. Med. 2005201(11):1837-1852)

Dosage and Administration

The compounds of the present invention may be formulated in a widevariety of oral administration dosage forms and carriers. Oraladministration can be in the form of tablets, coated tablets, dragées,hard and soft gelatine capsules, solutions, emulsions, syrups, orsuspensions. Compounds of the present invention are efficacious whenadministered by other routes of administration including continuous(intravenous drip) topical parenteral, intramuscular, intravenous,subcutaneous, transdermal (which may include a penetration enhancementagent), buccal, nasal, inhalation and suppository administration, amongother routes of administration. The preferred manner of administrationis generally oral using a convenient daily dosing regimen which can beadjusted according to the degree of affliction and the patient'sresponse to the active ingredient.

A compound or compounds of the present invention, as well as theirpharmaceutically useable salts, together with one or more conventionalexcipients, carriers, or diluents, may be placed into the form ofpharmaceutical compositions and unit dosages. The pharmaceuticalcompositions and unit dosage forms may be comprised of conventionalingredients in conventional proportions, with or without additionalactive compounds or principles, and the unit dosage forms may containany suitable effective amount of the active ingredient commensurate withthe intended daily dosage range to be employed. The pharmaceuticalcompositions may be employed as solids, such as tablets or filledcapsules, semisolids, powders, sustained release formulations, orliquids such as solutions, suspensions, emulsions, elixirs, or filledcapsules for oral use; or in the form of suppositories for rectal orvaginal administration; or in the form of sterile injectable solutionsfor parenteral use. A typical preparation will contain from about 5% toabout 95% active compound or compounds (w/w). The term “preparation” or“dosage form” is intended to include both solid and liquid formulationsof the active compound and one skilled in the art will appreciate thatan active ingredient can exist in different preparations depending onthe target organ or tissue and on the desired dose and pharmacokineticparameters.

The term “excipient” as used herein refers to a compound that is usefulin preparing a pharmaceutical composition, generally safe, non-toxic andneither biologically nor otherwise undesirable, and includes excipientsthat are acceptable for veterinary use as well as human pharmaceuticaluse. The compounds of this invention can be administered alone but willgenerally be administered in admixture with one or more suitablepharmaceutical excipients, diluents or carriers selected with regard tothe intended route of administration and standard pharmaceuticalpractice.

“Pharmaceutically acceptable” means that which is useful in preparing apharmaceutical composition that is generally safe, non-toxic, andneither biologically nor otherwise undesirable and includes that whichis acceptable for veterinary as well as human pharmaceutical use.

A “pharmaceutically acceptable salt” form of an active ingredient mayalso initially confer a desirable pharmacokinetic property on the activeingredient which were absent in the non-salt form, and may evenpositively affect the pharmacodynamics of the active ingredient withrespect to its therapeutic activity in the body. The phrase“pharmaceutically acceptable salt” of a compound means a salt that ispharmaceutically acceptable and that possesses the desiredpharmacological activity of the parent compound. Such salts include: (1)acid addition salts, formed with inorganic acids such as hydrochloricacid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, andthe like; or formed with organic acids such as acetic acid, propionicacid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvicacid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid,fumaric acid, tartaric acid, citric acid, benzoic acid,3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid,2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid,4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid,3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoicacid, salicylic acid, stearic acid, muconic acid, and the like; or (2)salts formed when an acidic proton present in the parent compound eitheris replaced by a metal ion, e.g., an alkali metal ion, an alkaline earthion, or an aluminum ion; or coordinates with an organic base such asethanolamine, diethanolamine, triethanolamine, tromethamine,N-methylglucamine, and the like.

Solid form preparations include powders, tablets, pills, capsules,cachets, suppositories, and dispersible granules. A solid carrier may beone or more substances which may also act as diluents, flavoring agents,solubilizers, lubricants, suspending agents, binders, preservatives,tablet disintegrating agents, or an encapsulating material. In powders,the carrier generally is a finely divided solid which is a mixture withthe finely divided active component. In tablets, the active componentgenerally is mixed with the carrier having the necessary bindingcapacity in suitable proportions and compacted in the shape and sizedesired. Suitable carriers include but are not limited to magnesiumcarbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin,starch, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, a low melting wax, cocoa butter, and the like.Solid form preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

Liquid formulations also are suitable for oral administration includeliquid formulation including emulsions, syrups, elixirs, aqueoussolutions, aqueous suspensions. These include solid form preparationswhich are intended to be converted to liquid form preparations shortlybefore use. Emulsions may be prepared in solutions, for example, inaqueous propylene glycol solutions or may contain emulsifying agentssuch as lecithin, sorbitan monooleate, or acacia. Aqueous solutions canbe prepared by dissolving the active component in water and addingsuitable colorants, flavors, stabilizing, and thickening agents. Aqueoussuspensions can be prepared by dispersing the finely divided activecomponent in water with viscous material, such as natural or syntheticgums, resins, methylcellulose, sodium carboxymethylcellulose, and otherwell known suspending agents.

The compounds of the present invention may be formulated for parenteraladministration (e.g., by injection, for example bolus injection orcontinuous infusion) and may be presented in unit dose form in ampoules,pre-filled syringes, small volume infusion or in multi-dose containerswith an added preservative. The compositions may take such forms assuspensions, solutions, or emulsions in oily or aqueous vehicles, forexample solutions in aqueous polyethylene glycol. Examples of oily ornonaqueous carriers, diluents, solvents or vehicles include propyleneglycol, polyethylene glycol, vegetable oils (e.g., olive oil), andinjectable organic esters (e.g., ethyl oleate), and may containformulatory agents such as preserving, wetting, emulsifying orsuspending, stabilizing and/or dispersing agents. Alternatively, theactive ingredient may be in powder form, obtained by aseptic isolationof sterile solid or by lyophilisation from solution for constitutionbefore use with a suitable vehicle, e.g., sterile, pyrogen-free water.

The compounds of the present invention may be formulated for topicaladministration to the epidermis as ointments, creams or lotions, or as atransdermal patch. Ointments and creams may, for example, be formulatedwith an aqueous or oily base with the addition of suitable thickeningand/or gelling agents. Lotions may be formulated with an aqueous or oilybase and will in general also containing one or more emulsifying agents,stabilizing agents, dispersing agents, suspending agents, thickeningagents, or coloring agents. Formulations suitable for topicaladministration in the mouth include lozenges comprising active agents ina flavored base, usually sucrose and acacia or tragacanth; pastillescomprising the active ingredient in an inert base such as gelatin andglycerin or sucrose and acacia; and mouthwashes comprising the activeingredient in a suitable liquid carrier.

The compounds of the present invention may be formulated foradministration as suppositories. A low melting wax, such as a mixture offatty acid glycerides or cocoa butter is first melted and the activecomponent is dispersed homogeneously, for example, by stirring. Themolten homogeneous mixture is then poured into convenient sized molds,allowed to cool, and to solidify.

The compounds of the present invention may be formulated for vaginaladministration. Pessaries, tampons, creams, gels, pastes, foams orsprays containing in addition to the active ingredient such carriers asare known in the art to be appropriate.

The compounds of the present invention may be formulated for nasaladministration. The solutions or suspensions are applied directly to thenasal cavity by conventional means, for example, with a dropper, pipetteor spray. The formulations may be provided in a single or multidoseform. In the latter case of a dropper or pipette, this may be achievedby the patient administering an appropriate, predetermined volume of thesolution or suspension. In the case of a spray, this may be achieved forexample by means of a metering atomizing spray pump.

The compounds of the present invention may be formulated for aerosoladministration, particularly to the respiratory tract and includingintranasal administration. The compound will generally have a smallparticle size for example of the order of five (5) microns or less. Sucha particle size may be obtained by means known in the art, for exampleby micronization. The active ingredient is provided in a pressurizedpack with a suitable propellant such as a chlorofluorocarbon (CFC), forexample, dichlorodifluoromethane, trichlorofluoromethane, ordichlorotetrafluoroethane, or carbon dioxide or other suitable gas. Theaerosol may conveniently also contain a surfactant such as lecithin. Thedose of drug may be controlled by a metered valve. Alternatively theactive ingredients may be provided in a form of a dry powder, forexample a powder mix of the compound in a suitable powder base such aslactose, starch, starch derivatives such as hydroxypropylmethylcellulose and polyvinylpyrrolidine (PVP). The powder carrier will form agel in the nasal cavity. The powder composition may be presented in unitdose form for example in capsules or cartridges of e.g., gelatin orblister packs from which the powder may be administered by means of aninhaler.

When desired, formulations can be prepared with enteric coatings adaptedfor sustained or controlled release administration of the activeingredient. For example, the compounds of the present invention can beformulated in transdermal or subcutaneous drug delivery devices. Thesedelivery systems are advantageous when sustained release of the compoundis necessary and when patient compliance with a treatment regimen iscrucial. Compounds in transdermal delivery systems are frequentlyattached to an skin-adhesive solid support. The compound of interest canalso be combined with a penetration enhancer, e.g., Azone(1-dodecylaza-cycloheptan-2-one). Sustained release delivery systems areinserted subcutaneously into to the subdermal layer by surgery orinjection. The subdermal implants encapsulate the compound in a lipidsoluble membrane, e.g., silicone rubber, or a biodegradable polymer,e.g., polyactic acid.

Suitable formulations along with pharmaceutical carriers, diluents andexcipients are described in Remington: The Science and Practice ofPharmacy 1995, edited by E. W. Martin, Mack Publishing Company, 19thedition, Easton, Pa. A skilled formulation scientist may modify theformulations within the teachings of the specification to providenumerous formulations for a particular route of administration withoutrendering the compositions of the present invention unstable orcompromising their therapeutic activity.

The modification of the present compounds to render them more soluble inwater or other vehicle, for example, may be easily accomplished by minormodifications (salt formulation, esterification, etc.), which are wellwithin the ordinary skill in the art. It is also well within theordinary skill of the art to modify the route of administration anddosage regimen of a particular compound in order to manage thepharmacokinetics of the present compounds for maximum beneficial effectin patients.

The term “therapeutically effective amount” as used herein means anamount required to reduce symptoms of the disease in an individual. Thedose will be adjusted to the individual requirements in each particularcase. That dosage can vary within wide limits depending upon numerousfactors such as the severity of the disease to be treated, the age andgeneral health condition of the patient, other medicaments with whichthe patient is being treated, the route and form of administration andthe preferences and experience of the medical practitioner involved. Fororal administration, a daily dosage of between about 0.01 and about 1000mg/kg body weight per day should be appropriate in monotherapy and/or incombination therapy. A preferred daily dosage is between about 0.1 andabout 500 mg/kg body weight, more preferred 0.1 and about 100 mg/kg bodyweight and most preferred 1.0 and about 10 mg/kg body weight per day.Thus, for administration to a 70 kg person, the dosage range would beabout 7 mg to 0.7 g per day. The daily dosage can be administered as asingle dosage or in divided dosages, typically between 1 and 5 dosagesper day. Generally, treatment is initiated with smaller dosages whichare less than the optimum dose of the compound. Thereafter, the dosageis increased by small increments until the optimum effect for theindividual patient is reached. One of ordinary skill in treatingdiseases described herein will be able, without undue experimentationand in reliance on personal knowledge, experience and the disclosures ofthis application, to ascertain a therapeutically effective amount of thecompounds of the present invention for a given disease and patient.

The pharmaceutical preparations are preferably in unit dosage forms. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

EXAMPLES

Commonly used abbreviations include: acetyl (Ac),azo-bis-isobutyrylnitrile (AIBN), atmospheres (Atm),9-borabicyclo[3.3.1]nonane (9-BBN or BBN),2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP), tert-butoxycarbonyl(Boc), di-tert-butyl pyrocarbonate or boc anhydride (BOC₂O), benzyl(Bn), butyl (Bu), Chemical Abstracts Registration Number (CASRN),benzyloxycarbonyl (CBZ or Z), carbonyl diimidazole (CDI),1,4-diazabicyclo[2.2.2]octane (DABCO), diethylaminosulfur trifluoride(DAST), dibenzylideneacetone (dba), 1,5-diazabicyclo[4.3.0]non-5-ene(DBN), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU),N,N′-dicyclohexylcarbodiimide (DCC), 1,2-dichloroethane (DCE),dichloromethane (DCM), 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ),diethyl azodicarboxylate (DEAD), di-iso-propylazodicarboxylate (DIAD),di-iso-butylaluminumhydride (DIBAL or DIBAL-H), di-iso-propylethylamine(DIPEA), N,N-dimethyl acetamide (DMA), 4-N,N-dimethylaminopyridine(DMAP), N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO),1,1′-bis-(diphenylphosphino)ethane (dppe),1,1′-bis-(diphenylphosphino)ferrocene (dppf),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI),2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ), ethyl (Et), ethylacetate (EtOAc), ethanol (EtOH), 2-ethoxy-2H-quinoline-1-carboxylic acidethyl ester (EEDQ), diethyl ether (Et₂O), ethyl isopropyl ether(EtOiPr), O-(7-azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluroniumhexafluorophosphate acetic acid (HATU), acetic acid (HOAc),1-N-hydroxybenzotriazole (HOBt), high pressure liquid chromatography(HPLC), iso-propanol (IPA), isopropylmagnesium chloride (iPrMgCl),hexamethyl disilazane (HMDS), hexanes (hex), liquid chromatography massspectrometry (LCMS), lithium hexamethyl disilazane (LiHMDS),meta-chloroperoxybenzoic acid (m-CPBA), methanol (MeOH), melting point(mp), MeSO₂-(mesyl or Ms), methyl (Me), acetonitrile (MeCN),m-chloroperbenzoic acid (MCPBA), mass spectrum (ms), methyl t-butylether (MTBE), methyl tetrahydrofuran (MeTHF), N-bromosuccinimide (NBS),n-Butyllithium (nBuLi), N-carboxyanhydride (NCA), N-chlorosuccinimide(NCS), N-methylmorpholine (NMM), N-methylpyrrolidone (NMP), pyridiniumchlorochromate (PCC), Dichloro-((bis-diphenylphosphino)ferrocenyl)palladium(II) (Pd(dppf)Cl₂), palladium(II) acetate (Pd(OAc)₂),tris(dibenzylideneacetone)dipalladium(0) (Pd₂(dba)₃), pyridiniumdichromate (PDC), phenyl (Ph), propyl (Pr), iso-propyl (i-Pr), poundsper square inch (psi), pyridine (pyr),1,2,3,4,5-Pentaphenyl-1′-(di-tert-butylphosphino)ferrocene (Q-Phos),room temperature (ambient temperature, rt or RT), sec-Butyllithium(sBuLi), tert-butyldimethylsilyl or t-BuMe₂Si (TBDMS),tetra-n-butylammonium fluoride (TBAF), triethylamine (TEA or Et₃N),2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO), triflate or CF₃SO₂-(Tf),trifluoroacetic acid (TFA),1,1′-bis-2,2,6,6-tetramethylheptane-2,6-dione (TMHD),O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU), thin layer chromatography (TLC), tetrahydrofuran (THF),trimethylsilyl or Me₃Si (TMS), p-toluenesulfonic acid monohydrate (TsOHor pTsOH), 4-Me-C₆H₄SO₂— or tosyl (Ts), andN-urethane-N-carboxyanhydride (UNCA). Conventional nomenclatureincluding the prefixes normal (n), iso (i), secondary (sec-), tertiary(tert-) and neo have their customary meaning when used with an alkylmoiety. (J. Rigaudy and D. P. Klesney, Nomenclature in OrganicChemistry, IUPAC 1979 Pergamon Press, Oxford.).

Preparation of I-1

Step 1. Preparation of 2-(6-chloropyridin-3-yl)propan-2-ol

A solution of 6-chloronicotinoyl chloride (38.037 g, 216 mmol, Eq: 1.00)in anhydrous diethyl ether (200 ml) was added dropwise to a stirred 3 Mmethylmagnesium iodide solution (158 ml, 475 mmol, Eq: 2.2) at roomtemperature. After the addition the reaction mixture was refluxed for 3hours. Reaction was quenched by pouring it to a stirred mixture ofice/200 ml acetic acid; sodium bicarbonate was added until pH 8;extracted with diethyl ether; washed with brine; dried over sodiumsulfate; filtered; concentrated to give a yellow solid (30.15 g, 0.175mol) MS (H+)=172.1

Step 2. Preparation of N-(2-(6-chloropyridin-3-yl)propan-2-yl)acetamide

2-(6-chloropyridin-3-yl)propan-2-ol (637 mg, 3.71 mmol, Eq: 1.00) wasdissolved in acetonitrile (5 ml). Acetic acid (2.9 g, 2.76 ml, 48.3mmol, Eq: 13) was added at room temperature and cooled after theaddition to 0° C. Sulfuric acid, concentrated (5.1 g, 2.77 ml, 52.0mmol, Eq: 14) was added dropwise to the solution, then allowed to warmup to room temperature and stirred over night. The reaction mixture waspoured into ice, concentrated NaOH solution was added until pH wasbasic; extracted with ethyl acetate; org. phase was washed with brine;dried with sodium sulfate; filtered to give a yellow solid. This residuewas triturated with ethyl acetate and a little bit hexane. Resultingprecipitate was filtered off to give a white solid (338 mg, 1.59 mmol).

MS (H+)=213.1

Step 3. Preparation of 2-(6-chloropyridin-3-yl)-N-ethylpropan-2-amine

N-(2-(6-chloropyridin-3-yl)propan-2-yl)acetamide (11.3 g, 53.1 mmol, Eq:1.00) was dissolved in anhydrous THF (350 ml) and refluxed. BMS (2M inTHF) (53.1 ml, 106 mmol, Eq: 2) was added dropwise to the solution andrefluxed over night. Conc. HCl solution (15 ml) was gently added to therefluxed reaction mixture and stirred for 1 hr. The reaction mixture wasconcentrated in vacuo.

The crude material was dissolved in dichloromethane/1 M HCl solution.Water phase was collected and treated with saturated sodium carbonatesolution; extracted with dichloromethane; org. phase was dried withsodium sulfate; filtered; concentrated. Crude product was purified bysilica gel chromatography to give a yellow gum (8.03 g, 40.4 mmol). Itwas used as is for the next step.

Step 4. Preparation of 5-(1-Ethylamino-1-methyl-ethyl)-pyridin-2-ylamine

2-(6-chloropyridin-3-yl)-N-ethylpropan-2-amine (5 g, 25.2 mmol, Eq:1.00) was dissolved in tetrahydrofuran (130 ml).2-(Dicyclohexylphosphino)biphenyl (1.76 g, 5.03 mmol, Eq: 0.2), thentris(dibenzylideneacetone)dipalladium(0) (2.3 g, 2.52 mmol, Eq: 0.1)were added under an argon atmosphere. Finally 1 M lithiumbis(trimethylsilyl)amide in THF (75.5 ml, 75.5 mmol, Eq: 3) was addeddropwise. The reaction mixture was stirred in a sealed flask at 90° C.overnight.

The reaction mixture was poured into sat NH₄Cl (200 ml) and extractedwith DCM (4×50 mL). The crude material was purified by flashchromatography (silica gel, 40 g, 0% to 15% MeOH (contains 0.5% NH4OH)in DCM to give a white solid (2.6 g, 14.5 mmol)

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.06 (t, J=1.00 Hz, 3H) 1.44 (s,6H) 1.86 (s, 1 H) 2.37 (q, J=1.00 Hz, 2H) 4.39 (s, 2H) 6.49 (d, J=1.00Hz, 1H) 7.55 (d, J=1.00 Hz, 1H) 8.08 (s, 1H)

Step 5. Preparation of6-chloro-4-[5-(1-ethylamino-1-methyl-ethyl)-pyridin-2-ylamino]-2-methyl-2H-pyridazin-3-one

This reaction was carried out under similar conditions to thosedescribed in step 6 of the preparation of I-6. After work up the productwas purified by preparative HPLC on silica gel, using a gradient of 2%to 8% methanol/methylene chloride. This provided the desired product asa yellow powder (328 mg). (M+H)⁺=322 m/e.

In a microwave reaction vial, added acetic acid2-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-6-chloro-benzyl ester(329 mg, 0.818 mmol), bis-pinaco-diboron (416 mg, 1.637 mmol), KOAc (241mg, 2.454 mmol) and Xphos (39 mg, 0.0818 mmol) and dioxane (4 mL).Bubble argon through for 15 min and then add Pd(dba)₂ (24 mg, 0.0409mmol). Seal the tube and heat it to 60° C. for 18 hrs. The reactionmixture was then diluted with EtOAc (5 mL) and washed with NaHCO₃(concentrated) (1×10 mL) and water (10 mL). The organic phase was thenconcentrated and purified on silica gel column with 25% EtOAc in Hex togive acetic acid2-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzylester as an yellow oil (330 mg, 81%).

Step 6. Preparation of acetic acid2-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-6-{5-[5-(1-ethylamino-1-methyl-ethyl)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-benzylester

This reaction was carried out under similar conditions to those in step7 of the preparation of I-6. After work up the product was purified bypreparative TLC (3 plates), eluting with 10% methanol/methylenechloride. This provided the desired product (together with somedes-acetyl product) as an orange-yellow foam (303 mg). (M+H)⁺=654 (612)m/e.

Example 1 Step 7. Preparation of6-tert-butyl-2-(3-{5-[5-(1-ethylamino-1-methyl-ethyl)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-2-hydroxymethyl-phenyl)-8-fluoro-2H-phthalazin-1-one

This reaction was carried out under similar conditions to those in step8 of the preparation of I-6. After work up the product was purified bypreparative HPLC on silica gel, using a gradient of 2% to 10%methanol*/methylene chloride (* methanol contains 2% ammoniumhydroxide). The product was collected and further purified bycrystallization from hot iso-propylacetate/hexanes. A crystallineproduct was collected by filtration, providing the desired product as alight yellow-white powder (341 mg). MP=229-233*C. (M+H)⁺=612 m/e. Page079. ¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.05 (t, J=7.18 Hz, 3H)1.32-1.59 (m, 15H) 2.38 (q, J=7.20 Hz, 2H) 3.81-4.05 (m, 4H) 4.43 (s,2H) 6.93 (d, J=8.31 Hz, 1 H) 7.39-7.82 (m, 6H) 8.28 (d, J=2.64 Hz, 2H)8.40 (d, J=2.27 Hz, 1H) 8.64 (s, 1H).

Preparation of I-2

6-Chloro-2-methyl-4-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-2H-pyridazin-3-one

6-aminopyridin-3-yl-morpholino-methanone (800 mg, 3.86 mmol, Eq: 1.00),4-bromo-6-chloro-2-methylpyridazin-3(2H)-one (1 g, 4.48 mmol, Eq: 1.16),cesium carbonate (4.4 g, 13.5 mmol, Eq: 3.5) and xantphos (335 mg, 579μmol, Eq: 0.15) were suspended in dioxane (40 ml). The suspension wasdegassed with argon. Finally Pd₂(dba)₃ (265 mg, 290 μmol, Eq: 0.075) wasadded and the reaction mixture was stirred at 90° C. over night under anargon atmosphere. The reaction mixture was allowed to cool to roomtemperature, and then filtered over celite. Filtrate was concentrated invacuo to give a light brown solid. The crude material was purified byflash chromatography (silica gel, 110 g, 0% to 10% MeOH in (EtOAc 1:1Hex) to afford a light yellow solid (408 mg, 1.17 mmol). MS (H⁺)=350.0¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 3.60-3.80 (m, 8H) 3.83 (s, 3H) 6.96(d, J=8.69 Hz, 1H) 7.77 (dd, J=8.50, 2.45 Hz, 1H) 8.35-8.44 (m, 2H) 8.47(d, J=2.27 Hz, 1H)

Example 2

6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one

6-chloro-2-methyl-4-(5-(morpholine-4-carbonyl)pyridin-2-ylamino)pyridazin-3(2H)-one(200 mg, 572 μmol, Eq: 1.00),2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate (525 mg, 743 μmol, Eq: 1.3) and cesium carbonate (652 mg, 2.00mmol, Eq: 3.5) were dissolved in 10% aq. dioxane solution (3.3 ml). Thereaction mixture was heated to 125° C. for 35 min in the microwave.Reaction mixture was filtered over celite. Filtrate was extracted withethyl acetate, washed with water, and then with brine. Organic phase wasdried over sodium sulfate; filtered; concentrated to give 640 mg of alight brown solid. The crude material was dissolved in ethyl acetate,and treated with hexane until a precipitate was formed. Precipitate wascollected by filtration to give 354 mg of an off-white solid. Solid wasdissolved in dioxane (3 ml) and 1 M sodium hydroxide solution (858 μA,858 μmol, Eq: 1.5) was added and stirred at room temperature overnight.

The reaction mixture was loaded into a 24 g column and purified by flashchromatography (silica gel, 24 g, 0-13% MeOH in (EtOAc 1:1 Hex)) to give194 mg of an off-white solid. Drying under high vacuum afforded anoff-white crystalline product (178 mg, 278 μmol)

m.p.=215-220° C. MS (H⁺)=640.1

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.44 (s, 9H) 3.63-3.79 (m, 8H) 3.93(s, 3H) 4.44 (s, 2H) 7.05 (d, 1H) 7.45-7.69 (m, 5H) 7.75-7.82 (d, 1H)8.29 (d, J=2.64 Hz, 1H) 8.43 (s, 1H) 8.54 (s, 1H) 8.68 (s, 1H).

Preparation of I-3

6-Chloro-4-(5-methanesulfonyl-pyridin-2-ylamino)-2-methyl-2H-pyridazin-3-one

4-bromo-6-chloro-2-methylpyridazin-3(2H)-one (1 g, 4.48 mmol, Eq: 1.00),5-(methylsulfonyl)pyridin-2-amine (771 mg, 4.48 mmol, Eq: 1),4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (388 mg, 671 μmol, Eq:0.15) and cesium carbonate (5.1 g, 15.7 mmol, Eq: 3.5) were suspended indioxane (80.0 ml). Finally tris (dibenzylideneacetone)dipalladium(0)(307 mg, 336 μmol, Eq: 0.075) was added. The reaction mixture was heatedto 90° C. over night.

Reaction mixture was filtered over celite; washed with dioxane;concentrated. Crude material was triturated with dichloromethane andprecipitate was collected by filtration to afford an off-white solid (70mg, 222 μmol)

¹H NMR (300 MHz, DMSO-d₆) δ ppm 3.25 (s, 3H) 3.69 (s, 3H) 7.73 (d,J=8.69 Hz, 1H) 8.16 (dd, J=1.00 Hz, 1H) 8.42 (s, 1H) 8.83 (d, J=2.27 Hz,1H)

Example 3

6-tert-Butyl-8-fluoro-2-[2-hydroxymethyl-3-[5-(5-methanesulfonyl-pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl]-phenyl}-2H-phthalazin-1-one

6-Chloro-4-(5-methanesulfonyl-pyridin-2-ylamino)-2-methyl-2H-pyridazin-3-one(40 mg, 127 μmol, Eq: 1.00),2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate (136 mg, 165 μmol, Eq: 1.3) and cesium carbonate (145 mg, 445μmol, Eq: 3.5) were dissolved in 10% aq. dioxane solution (3.3 ml). Thereaction mixture was heated to 130° C. for 30 min in the microwave.Reaction mixture was filtered over celite. Filtrate was extracted withethyl acetate, washed with water, and then with brine. Organic phase wasdried over sodium sulfate; filtered; concentrated to give light brownsolid. The crude material was dissolved in ethyl acetate, and treatedwith hexane until a precipitate was formed. Precipitate was collected byfiltration to give an off-white solid. Solid was dissolved in dioxane (2ml) and 1 M sodium hydroxide solution (191 μl, 191 μmol, Eq: 1.5) wasadded and stirred at room temperature overnight.+

The reaction mixture was loaded into a 12 g column and purified by flashchromatography (silica gel, 12 g, 0-13% MeOH in (EtOAc 1:1 Hex)) to givean off-white solid (39 mg, 64.5 μmol) m.p.=225-230° C. MS (H⁺)=605.3

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.36 (s, 9H) 3.03 (s, 3H) 3.87 (s,3H) 4.38 (s, 2H) 7.00 (d, J=1.00 Hz, 1H) 7.40-7.61 (m, 5H) 8.02 (d,J=1.00 Hz, 1H) 8.22 (s, 1H) 8.56 (br. s., 1H) 8.73 (s, 1H) 8.83 (br. s.,1H).

Preparation of I-4

2-Chloro-5-(3-methoxy-azetidin-1-ylmethyl)-pyridine: To a slurry ofmethoxy azetidine HCL salt (24.2 g, 198 mmol, Eq: 1.00) in 400 mL ofmethylene chloride was added triethylamine (24.0 g, 33.1 ml, 237 mmol,Eq: 1.2). The precipitate formed went back into solution. Next6-chloronicotinaldehyde (28 g, 198 mmol, Eq: 1.00) and acetic acid (22.6ml, 396 mmol, Eq: 2.0) was added. Finally sodium triacetoxyhydroborate(41.9 g, 198 mmol, Eq: 1.00) was added in portions. The first 11 g wereadded and waited for the chunks to disperse. The second 11 g were thenadded and an aliquot was checked by TLC. Added the remainder still inportions and continued stirring the slurry. After completion ofaddition, by TLC, some aldehyde seems to remain so stirring wascontinued. After another 30 minutes it looked essentially done. Added400 mL of water and an additional 200 mL of methylene chloride andseparated layers. The aqueous phase was made basic with ˜400 mL of 1.0MNaOH and then extracted with 3 times 400 mL of methylene chloride.Concentrated to afford a thick colorless oil. Pumped down to constantweight 28.3 g (67.3%).

5-(3-Methoxy-azetidin-1-ylmethyl)-pyridin-2-ylamine: To a round bottomedflask charged with 2-chloro-5-((3-methoxyazetidin-1-yl)methyl)pyridine(11.5 g, 54.1 mmol, Eq: 1.00), tris(dibenzylideneacetone)dipalladium(0)(1.24 g, 1.35 mmol, Eq: 0.025), and biphenyl-2-yldicyclohexylphosphine(948 mg, 2.7 mmol, Eq: 0.05) was added toluene (150 ml) followedimmediately by lithium bis(trimethylsilyl)amide (81.1 ml, 81.1 mmol, Eq:1.5) as a 1.0 M solution in THF. Brought quickly to reflux and stirredovernight under Argon. Next day, the reaction was checked by TLC(9:1MC:MeOH) and the starting material was gone, replaced primarily by asingle lower R_(f) spot. Cooled while stirring and added 5 ml of 1.0MHCl. Stirred 20 min and filtered over celite. The filtrate was dilutedwith ether and washed with 200 mL of 1.0M NaOH followed by water andbrine. Dried the org phase over sodium sulfate, filtered and removedsolvent. Obtained a dark red oil weighing 14.4 g. Took the oil up inCH₂Cl₂ and flashed (neat MC to 90:10 MC:MeOH:0.1 Et3N). Collected 4.4 g(42.1%) of cleanest fractions as a reddish oil for next step.

6-Chloro-4-[5-(3-methoxy-azetidin-1-ylmethyl)-pyridin-2-ylamino]-2-methyl-2H-pyridazin-3-one:5-(3-Methoxy-azetidin-1-ylmethyl)-pyridin-2-ylamine (130 mg, 0.67 mmol,Eq: 1.0), 4-bromo-6-chloro-2-methyl-2H-pyridazin-3-one (165 mg, 223mmol, Eq: 1.1), xantphos (58 mg, 0.1 mmol, Eq: 0.15),tris(dibenzylideneacetone)dipalladium(0) (46 mg, 0.05 mmol, Eq: 0.075)and cesium carbonate (767 mg, 2.35 mmol, Eq: 3.5) were added to amicrowave vial. The vial was capped and purged with argon. Degasseddioxane (4.5 ml) was added to the vial through the septum and the vialwas purged again, then backfilled with argon. The reaction was heated at90° C. overnight in a sand bath. The crude reaction mixture was filteredthrough celite and purified by chromatography using a gradient of 5% to25% methanol in DCM with a little added ammonium hydroxide to give 150mg of product (63.7%).

Acetic acid2-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-6-{5-[5-(3-methoxy-azetidin-1-ylmethyl)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-benzylester:6-Chloro-4-[5-(3-methoxy-azetidin-1-ylmethyl)-pyridin-2-ylamino]-2-methyl-2H-pyridazin-3-one(100 mg, 0.29 mmol, Eq: 1.0), acetic acid2-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzylester (247 mg, 0.5 mmol, Eq: 1.75), bis(dibenzylideneacetone)palladium(8.2 mg, 0.014 mmol, Eq: 0.05), x-phos (13.6 mg, 0.028 mmol, Eq: 0.10),and tripotassium phosphate (121 mg, 0.57 mmol, Eq: 2.0) were added to amicrowave vial. The vial was capped and purged with nitrogen. Butanol(2.3 ml) and water (0.5 ml) were added and the vial was purged again,then backfilled with nitrogen. The reaction was heated at 110° C. for2.5 hrs in a sand bath. The crude reaction was filtered through celiteand purified by chromatography using a gradient of 0% to 25% methanol inDCM. Fractions containing the desired product were combined with thosein which the acetate protecting group had been removed during the courseof the reaction to give 175 mg of material (approximately 92%).

Example 4

6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{5-[5-(3-methoxy-azetidin-1-ylmethyl)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one:Acetic acid2-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-6-{5-[5-(3-methoxy-azetidin-1-ylmethyl)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-benzylester (175 mg, 0.26 mmol, Eq: 1.0) was dissolved in 2.6 ml of THF.Sodium hydroxide (1.3 ml of a 1.0M solution in water, 1.3 mmol, Eq: 5.0)was added dropwise. The reaction was stirred at room temperatureovernight. Starting material was still present the next morning. Thereaction was heated at 50° C. for two hours at which point no startingmaterial remained. The reaction was diluted with ethyl acetate and waterand the layers were separated. The organic layer was dried andconcentrated. The residue was triturated with isopropyl acetate,filtered, washed with ether, and dried in a vacuum oven to give 75 mg(45.7%) of the desired product as a white powder. ¹H NMR (300 MHz,DMSO-d6) δ ppm 1.37 (s, 9H) 2.79 (t, J=6.80 Hz, 2H) 3.11 (s, 3H)3.37-3.44 (m, 2H) 3.46 (s, 2H) 3.77 (s, 3H) 3.92 (t, J=5.85 Hz, 1H) 4.40(br.s., 2H) 4.52-4.63 (m, 1H) 7.40-7.62 (m, 5H) 7.74 (d, J=13.22 Hz, 1H)7.86 (s, 1H) 8.15 (s, 1H) 8.48-8.55 (m, 2H) 9.36-9.44 (m, 1H). MS:(M+H)⁺=626. MP=140-142° C.

Preparation of I-5 Example 5

6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(8-methyl-3,8-diaza-bicyclo[3.2.1]oct-3-ylmethyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-onewas prepared using the general procedure described for preparation ofcompound I-4, substituting 8-methyl-3,8-diazabicyclo[3.2.1]octanedihydrochloride for methoxy azetidine HCL salt in the first step of thesynthesis and using 2.5 equivalents of triethyl amine to free base thedihydrochloride salt. The resulting benzyl amine intermediate wascarried through the remaining steps of the synthesis to give 65 mg offinal product as a white powder. ¹H NMR (300 MHz, DMSO-d6) δ9.38 (s,1H), 8.48-8.54 (m, 2H), 8.10-8.17 (m, 1H), 7.86 (s, 1H), 7.74 (d,J=13.22 Hz, 1H), 7.55-7.62 (m, 1H), 7.42-7.55 (m, 4H), 4.53-4.60 (m,1H), 4.39 (br. s., 2H), 3.77 (s, 3H), 2.93 (br. s., 2H), 2.41 (d, J=7.93Hz, 2H), 2.15 (d, J=10.20 Hz, 2H), 2.09 (s, 3H), 1.78 (d, J=4.91 Hz,2H), 1.62 (d, J=6.80 Hz, 2H), 1.37 (s, 9H). MS: (M+H)⁺=665.

MP=162-165° C.

Preparation of I-6

Step 1. Preparation of ethyl2-(6-chloropyridin-3-yloxy)-2-methylpropanoate

To a solution of 6-chloropyridin-3-ol (5 g, 38.6 mmol) andethyl-2-bromo-2-methylpropanoate (6.01 ml, 40.5 mmol) in acetonitrile(50 mL) was added cesium carbonate (27 g, 83 mmol). The material wasstirred vigorously for 48 hours. The mixture was taken up in water (100ml) and ethyl acetate (100 ml) and transferred to a separatory funneland shaken. The organic phase was collected and the aqueous phase wasback extracted with ethyl acetate (2×50 mL). The organic phases werecombined, dried (magnesium sulfate), filtered and stripped. The crudematerial was purified via preparative HPLC (silica gel; 50 g column)eluting with 5-30% ethyl acetate/hexanes to provide the desired productas light white-yellow mobile oil (6.78 g).

(M+H)⁺=244 m/e.

Step 2. Preparation of 2-(6-chloropyridin-3-yloxy)-2-methylpropan-1-ol

A solution of ethyl 2-(6-chloropyridin-3-yloxy)-2-methylpropanoate(6.093 g, 25.0 mmol) in dry tetrahydrofuran (80 mL) is cooled to −20° C.(acetonitrile/dry ice bath) under nitrogen atmosphere. A solution oflithium aluminum hydride (1.0 M in THF, 35 ml) was added via drop-wiseaddition over 10 minutes. The mixture was stirred at −20° C. for 1 hour.The reaction was carefully quenched via addition of water (0.73 ml). Themixture was stirred for 10 minutes and then an aqueous solution of 5%sodium hydroxide (1.34 ml) was added with stirring for 10 minutes.Finally water (1.34 ml) was added and the mixture was stirred for 10additional minutes. Magnesium sulfate was added and the material wasfiltered through a plug of celite, rinsing well with tetrahydrofuran.(Note that subsequent stirring of the aluminum salts in dichloromethane(50 ml) and filtering through celite provides additional product). Thefiltrates were stripped on the rotary evaporator, providing the desiredproduct as a semi-viscous brown oil (4.843 g). (M+H)⁺=202 m/e.

Step 3. Preparation of 2-(6-chloropyridin-3-yloxy)-2-methylpropanal

An oven dried flask (50 ml, round bottom) containing dry dichloromethane(13 ml) is cooled to −78° C. (dry ice/acetone bath) under argonatmosphere. Oxalyl chloride (0.23 ml, 2.67 mmol) is added followed bythe addition of dry dimethyl sulfoxide (0.31 ml, 4.31 mmol) viadrop-wise addition. The mixture is stirred for 10 minutes and then asolution of 2-(6-chloropyridin-3-yloxy)-2-methylpropan-1-ol (451 mg,2.06 mmol) [dissolved in dichloromethane (4 ml)] is added via slowdrop-wise addition. The cooled solution was stirred for 30 minutes andthen triethylamine (1.15 ml, 8.2 mmol) was added and the cooling bathwas removed. The mixture was stirred and warmed to ambient over 1 hour.A saturated solution of sodium bicarbonate (20 ml) was added and alsodichloromethane (20 ml). The material was transferred and shaken in areparatory funnel. The dichloromethane phase was collected and washedwith brine solution (25 mL). The aqueous phase was back extracted withmethylene chloride (2×20 mL) and the organic phases combined, dried overmagnesium sulfate, filtered and stripped. The material was purified byfiltration through a short column of silica gel (20 g), eluting with 30%ethyl acetate/hexanes, which provided the product as a light yellow oil(361 mg). (M+H)⁺=200 m/e.

Step 4. Preparation of2-(6-chloropyridin-3-yloxy)-N,N,2-trimethylpropan-1-amine

To a large capacity microwave tube containing2-(6-chloropyridin-3-yloxy)-2-methylpropanal (354 mg, 1.77 mmol) andsodium triacetoxyborohydride (940 mg, 4.43 mmol) in dry dichloromethane(4 ml) was added glacial acetic acid (0.81 ml, 14.2 mmol) followed by a2 M solution of dimethylamine (14.2 ml, 28.4 mmol, in tetrahydrofuran).The tube was capped and heated to 50° C. (oil bath) with vigorousstirring for 16 hours. The mixture was cooled to ambient and thecontents poured into a separatory funnel containing an aqueous solutionof saturated sodium bicarbonate (30 ml). Dichloromethane (30 ml) wasadded and the mixture was shaken. The contents were filtered through aplug of celite, washing well with dichloromethane. The filtrate wascollected and washed with a brine solution (40 ml). The dichloromethanephase was collected and the aqueous phase was back extracted withmethylene chloride (2×40 mL). The organic phases were combined, driedover magnesium sulfate, filtered and stripped. The material was purifiedby preparative thin layer chromatography (2 plates), eluting with 1.8%methanol/dichloromethane. The plates were then re-developed with 2.6%methanol/dichloromethane, and the product band was collected whichprovided the desired as a light yellow mobile oil, which slowlysolidified on standing (255 mg). (M+H)⁺=229 m/e.

Step 5. Preparation of 4-bromo-6-chloro-2-methylpyridazin-3(2H)-one

To a solution of2-(6-chloropyridin-3-yloxy)-N,N,2-trimethylpropan-1-amine (255 mg, 1.11mmol) in dry tetrahydrofuran (6.6 ml) was added2-(dicyclohexylphosphino)biphenyl (78 mg, 0.22 mmol) followed bytris(dibenzylideneacetone)dipalladium (0) (102 mg, 0.11 mmol). Themixture was vacuum de-gassed and placed under argon atmosphere. A 1Msolution of lithium bis(trimethylsilyl)amide (3.34 ml, intetrahydrofuran) was added and the tube was sealed and heated to 75° C.(oil bath) with vigorous stirring overnight. The mixture was cooled toambient and the contents poured into a separatory funnel containing asaturated aqueous solution of ammonium chloride (25 ml). Dichloromethane(30 ml) was added and the mixture was shaken. The organic phase wascollected and the aqueous phase was back extracted with methylenechloride (4×50 mL). The methylene chloride phases were combined, driedover magnesium sulfate, filtered and stripped. The material was purifiedby preparative thin layer chromatography (2 plates), eluting with 8%methanol/dichloromethane. A polar band was collected which provided theproduct as a red-brown viscous oil (229 mg). Material was used “as is”in the next step.

Step 6. Preparation of6-chloro-4-(5-(1-(dimethylamino)-2-methylpropan-2-yloxy)pyridin-2-ylamino)-2-methylpyridazin-3(2H)-one

A solution of 4-bromo-6-chloro-2-methylpyridazin-3(2H)-one (282 mg, 1.26mmol), 5-(1-(dimethylamino)-2-methylpropan-2-yloxy)pyridin-2-amine (203mg, 0.97 mmol), Xantphos (84 mg, 0.15 mmol) and cesium carbonate (1.11g, 3.39 mmol) in dry dioxane (6.6 ml) was vacuum de-gassed and placeunder argon atmosphere. To this mixture was addedtris(dibenzylideneacetone)dipalladium (0) (67 mg, 0.073 mmol) and thevacuum de-gas cycle was repeated. The material was heated at 90° C. (oilbath) with vigorous stirring overnight. The flask was cooled to ambientand the contents were filtered through a plug of celite, rinsing wellwith dioxane. The volatiles were stripped and the crude was purified bypreparative thin layer chromatography (4 plates), eluting first with 6%and then re-developing with 8% methanol/dichloromethane. The productband was collected which provided the desired as a light brown powder(196 mg). (M+H)⁺=352 m/e.

In a microwave reaction vial, added acetic acid2-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-6-chloro-benzyl ester(329 mg, 0.818 mmol), bis-pinaco-diboron (416 mg, 1.637 mmol), KOAc (241mg, 2.454 mmol) and Xphos (39 mg, 0.0818 mmol) and dioxane (4 mL).Bubble argon through for 15 min and then add Pd(dba)2 (24 mg, 0.0409mmol). Seal the tube and heat it to 60° C. for 18 hrs. The reactionmixture was then diluted with EtOAc (5 mL) and washed with NaHCO₃(concentrated) (1×10 mL) and water (10 mL). The organic phase was thenconcentrated and purified on silica gel column with 25% EtOAc in Hex togive acetic acid2-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzylester as an yellow oil (330 mg, 81%).

Step 7. Preparation of acetic acid2-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-6-{5-[5-(2-dimethylamino-1,1-dimethyl-ethoxy)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-benzylester

A flask was charged with2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate (391 mg, 0.55 mmol),6-chloro-4-(5-(1-(dimethylamino)-2-methylpropan-2-yloxy)pyridin-2-ylamino)-2-methylpyridazin-3(2H)-one(150 mg, 0.43 mmol), X-phos (31 mg, 0.06 mmol) and potassium phosphatetribasic (199 mg, 0.94 mmol). The mixture was taken up in n-butanol (2.8ml) and water (0.67 ml) and vacuum de-gassed and placed under argonatmosphere. To this mixture was added bis(dibenzylideneacetone)palladium(17 mg, 0.03 mmol) and the vacuum de-gas cycle was repeated. Thematerial was heated at 110° C. (oil bath) with vigorous stirring underargon atmosphere for 2.5 hours. The flask was cooled to ambient and thecontents were taken up in water (35 ml) and ethyl acetate (35 ml). Thecontents were transferred to a separatory funnel and shaken. The organicphase was collected and washed with water (35 ml). The aqueous phaseswere back extracted with ethyl acetate (2×30 ml) and the organic phasescombined, dried (magnesium sulfate), filtered and stripped. Theremainder was purified by preparative thin layer chromatography (3plates), eluting with 8% methanol/dichloromethane to provide desiredproduct (together with some des-acetyl product) as a golden brown oil(312 mg). (M+H)⁺=684 (642) m/e.

Example 6 Step 8. Preparation of6-tert-Butyl-2-(3-{5-[5-(2-dimethylamino-1,1-dimethyl-ethoxy)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-2-hydroxymethyl-phenyl)-8-fluoro-2H-phthalazin-1-one

To a solution of2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(5-(5-(1-(dimethylamino)-2-methylpropan-2-yloxy)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-benzylacetate (292 mg, 0.43 mmol) in dioxane (1.5 ml) was added a solution of2N sodium hydroxide (2.5 ml, 5 mmol). The flask was heated at 50° C.(oil bath) with vigorous stirring under argon atmosphere for 3 hours.The material was cooled to ambient and the contents were taken up inwater (25 ml) and methylene chloride (50 ml) and transferred to areparatory funnel and shaken. The organic phase was collected and washedwith a solution of 50% diluted brine (25 ml). The aqueous phases wereback extracted with methylene chloride (2×40 ml) and the organic phasescombined, dried (magnesium sulfate), filtered and stripped. Theremainder was purified by preparative thin layer chromatography (3plates), eluting with 6% methanol/dichloromethane and then re-developingthe plates with first 8% and then 11% methanol/dichloromethane. Theproduct band was collected providing the desired product as a lightyellow-white solid (72 mg). MP=136-144° C.; (M+H)⁺=642 m/e. ¹H NMR (300MHz, CHLOROFORM-d) δ ppm 1.28 (s, 6H) 1.42 (s, 9H) 2.40 (s, 6H) 2.51 (s,2H) 3.90 (s, 3H) 4.42 (s, 2H) 6.90 (d, J=9.06 Hz, 1H) 7.33 (dd, J=8.69,3.02 Hz, 1H) 7.41-7.72 (m, 5H) 8.09 (d, J=3.02 Hz, 1H) 8.20-8.35 (m, 2H)8.53 (s, 1H).

Preparation of I-7 Example 7

2-{3-[5-(5-Azetidin-1-ylmethyl-pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl]-2-hydroxymethyl-phenyl}-6-tert-butyl-8-fluoro-2H-phthalazin-1-onewas prepared using the general procedure described for compound I-4,substituting azetidine for methoxy azetidine HCL salt in the first stepand omitting the use of triethyl amine. The resulting benzyl amineintermediate was carried through the remaining steps of the synthesis togive 35 mg of final product as an off-white powder. ¹H NMR (300 MHz,DMSO-d6) δ9.37 (s, 1H), 8.47-8.56 (m, 2H), 8.15 (s, 1H), 7.86 (s, 1H),7.74 (d, J=13.22 Hz, 1H), 7.40-7.63 (m, 5H), 4.51-4.62 (m, 1H), 4.40(br. s., 2H), 3.77 (s, 3H), 3.40 (s, 2H), 3.06 (t, J=6.80 Hz, 4H), 1.92(quin, J=6.89 Hz, 2H), 1.37 (s, 9H). MS: (M+H)⁺=596. MP=160-163° C.

Preparation of I-8 Example 8

6-tert-Butyl-2-{3-[5-(5-dimethylaminomethyl-pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl]-2-hydroxymethyl-phenyl}-8-fluoro-2H-phthalazin-1-onewas prepared using the general procedure described for the preparationof compound I-4, except that the first step was omitted since(6-chloro-pyridin-3-ylmethyl)-dimethyl-amine is commercially available.This compound was carried through the remaining steps of the synthesisto give 120 mg of final product as an off-white powder. ¹H NMR (300 MHz,DMSO-d6) δ ppm 9.40 (s, 1H) 8.47-8.57 (m, 2H) 8.15 (s, 1H) 7.86 (s, 1H)7.74 (d, J=13.2 Hz, 1H) 7.56-7.65 (m, 1H) 7.42-7.56 (m, 4H) 4.52-4.61(m, 1H) 4.40 (br. s., 2H) 3.77 (s, 3H) 3.34-3.40 (s, 2H, occluded byDMSO water peak) 2.10 (s, 6H) 1.37 (s, 9H). MS: (M+H)⁺=584. MP=170-174°C.

Preparation of I-9

tert-butyl8-(6-nitropyridin-3-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate

Triethylamine (6.87 mL, 49.3 mmol) was added to a stirred solution of5-fluoro-2-nitropyridine (700 mg, 4.93 mmol) and (1R,5S)-tert-butyl3,8-diazabicyclo[3.2.1]octane-3-carboxylate (1.05 g, 4.93 mmol) in 8 mLof DMSO at room temperature. The reaction mixture was heated to 80° C.for 2 hr. After cooling to room temperature, the reaction mixture wasdiluted with ethyl acetate, washed with, saturated ammonium chloride,water (3×), dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo to afford 1.21 g (73.5%) of tert-butyl8-(6-nitropyridin-3-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate asyellow solid.

tert-butyl8-(6-aminopyridin-3-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate

To a solution of tert-butyl8-(6-nitropyridin-3-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (330mg, 987 umol) in 10 ml of Methanol was added 10% Palladium in carbon (10mg. The reaction mixture was hydrogenated 2 hr under 50 psi hydrogen.The reaction mixture was filtered through pack of celite andconcentrated to afford 300 mg (100%) of tert-butyl8-(6-aminopyridin-3-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate ascolorless oil. This product was used in subsequent steps without furtherpurification.

(1R,5S)-tert-butyl8-(6-(6-chloro-2-methyl-3-oxo-2,3-dihydropyridazin-4-ylamino)pyridin-3-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate

This reaction was carried out under similar conditions to thosedescribed above in step 6 of preparation of Example 6. After work up theproduct was purified by preparative HPLC on silica gel, using a gradientof 2% to 8% methanol/methylene chloride. This provided the desiredproduct as a light yellow solid (275 mg 62.4%). (M+H)⁺=447.2 m/e.

tert-butyl8-(6-(6-(2-(acetoxymethyl)-3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)phenyl)-2-methyl-3-oxo-2,3-dihydropyridazin-4-ylamino)pyridin-3-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate

This reaction was carried out under similar conditions to thosedescribed above in step 7 of preparation of Example 6.(1R,5S)-tert-butyl8-(6-(6-chloro-2-methyl-3-oxo-2,3-dihydropyridazin-4-ylamino)pyridin-3-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate(100 mg, 224 umol),2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate (114 mg, 224 umol), xPhos (10.7 mg, 22.4 umol) and potassiumphosphate (119 mg, 559 umol) in 7 ml of Dioxane/water (9:1) was degassedwith nitrogen for 10 minutes and bis(dibenzylideneacetone)palladium (0)(6.42, 11.2 umol) was added. The reaction mixture was heated to 100° C.for 2 hr. After work up, the product was purified by preparative HPLC onsilica gel, using a gradient of 5% to 70% ethylacetate/hexane. Thisprovided the desired product as a light yellow solid (105 mg 60.3%).(M+H)⁺=779 m/e.

tert-butyl8-(6-(6-(3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-2-(hydroxymethyl)phenyl)-2-methyl-3-oxo-2,3-dihydropyridazin-4-ylamino)pyridin-3-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate

This reaction was carried out under similar conditions to thosedescribed above in step 8 of the preparation for I-6. After work up, theproduct was crystallized as light yellow powder (90 mg, 90.6%).(M+H)⁺=737 m/e.

Example 92-(3-(5-(5-(3,8-diazabicyclo[3.2.1]octan-8-yl)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-(hydroxymethyl)phenyl)-6-tert-butyl-8-fluorophthalazin-1(2H)-one

tert-butyl8-(6-(6-(3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-2-(hydroxymethyl)phenyl)-2-methyl-3-oxo-2,3-dihydropyridazin-4-ylamino)pyridin-3-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate(90 mg, 122 umol) was de-BOC with 50% trifluoro acid in dichloromethane(10 mL) for 2 hr. The reaction mixture was concentrated to dryness, thenpartitioned between ethyl acetate and saturated sodium bicarbonate. Theorganic phase was dried over sodium sulfate, filtered and concentrated.

The product was collected and further purified by crystallization fromhot iso-propylacetate/hexanes. A crystalline product was collected byfiltration, providing the desired product as a light brown powder (53mg, 68.1%). (M+H)⁺=638 m/e. ¹H NMR (500 MHz, DMSO-d₆) δ 9.13 (s, 1H),8.49 (d, J=2.44 Hz, 1H), 8.31-8.35 (m, 1H), 7.90 (d, J=2.44 Hz, 1H),7.85 (d, J=1.95 Hz, 1H), 7.73 (d, J=11.71 Hz, 1H), 7.49-7.55 (m, 1H),7.43-7.48 (m, 2H), 7.37 (d, J=8.79 Hz, 1H), 7.27 (dd, J=2.93, 9.27 Hz,1H), 4.48-4.56 (m, 1H), 4.38 (d, J=11.23 Hz, 3H), 4.04-4.15 (m, 2H),3.69-3.79 (m, 3H), 2.93 (d, J=12.20 Hz, 2H), 2.42-2.46 (m, 2H),1.82-1.93 (m, 4H), 1.36 (s, 9H)

Preparation of I-10 Step 1

To a 15 mL microwave vial was added methy 6-aminonicotinate (170 mg,1.12 mmol, Eq: 1.00), 4-bromo-6-chloro-2-methylpyridazin-3(2H)-one (250mg, 1.12 mmol, Eq: 1.00), Cs₂CO₃ (1.28 g, 3.92 mmol, Eq: 3.5) andxantphos (97.1 mg, 168 μmol, Eq: 0.15) in Dioxane (8 ml). The reactionwas purged with argon and Pd₂(dba)₃ (76.8 mg, 83.9 μmol, Eq: 0.075) wasadded. The vial was capped and heated in the microwave at 90° C. for 30min. LC-MS at t=30 min showed the reaction was incomplete with startingmaterial remaining. The reaction was heated further at 120° C. for 30mins. The sample had solidified. The crude mixture was taken up in DCMand stripped to a dark brown oily solid. The residue was taken up in DCMand washed with water. The aqueous layer was back-extracted with DCM(2×50 mL). The organic layers were combined, washed with sat NaCl (1×25mL), dried over Na₂SO₄ and concentrated in vacuo. LC-MS of crude orgphase showed mainly product.

The crude material was triturated with DCM and cooled. The tan solid wasfiltered and washed with a minimum amount of cold DCM. The solid wasdried under vacuum to give 158 mg of a light tan solid in 48% yield. 1HNMR in DMSO-d6 is consistent with desired product.

MS (m+1)=295.0.

Step 2

To a 15 mL microwave vial was added methyl6-(6-chloro-2-methyl-3-oxo-2,3-dihydropyridazin-4-ylamino)nicotinate(153 mg, 519 μmol, Eq: 1.00),2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate (334 mg, 675 μmol, Eq: 1.3) and Cs₂CO₃ (592 mg, 1.82 mmol, Eq:3.5) in Dioxane (5 ml) and Water (0.5 ml). PdDCl2(DPPF) (42.4 mg, 51.9μmol, Eq: 0.1) was added and the suspension was purged with argon. Thevial was capped and heated in the microwave at 120° C. for 30 min. LC-MSat t=30 min showed the reaction was complete. Diluted with DCM andfiltered through celite. The yellow filtrate was stripped in vacuo to atan solid. The material was not very soluble in DCM. The crude materialwas used as is in the subsequent hydrolysis.

Step 3

In a 250 mL round-bottomed flask, methyl6-(6-(2-(acetoxymethyl)-3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)phenyl)-2-methyl-3-oxo-2,3-dihydropyridazin-4-ylamino)nicotinate(325 mg, 519 μmol, Eq: 1.00) was combined with Dioxane (10 ml) and 1MLiOH (3 ml) to give a yellow solution containing a small amount ofinsoluble fine granules. The reaction mixture was stirred at 25° C. for17 h. LC-MS at t=17 h showed the reaction was complete. Quenched withsmall amount of 1M HCl (acidic pH ˜1) and diluted with EtOAc. Separatedthe phases and the aqueous layer was back-extracted with EtOAc (2×25mL). The combined organic layers were dried over Na₂SO₄ and concentratedin vacuo to a light tan solid. The solid was dried under vacuum to give34 mg of a light tan powder in 12% yield. 1H NMR in CDCl₃ is consistentwith desired product. MS (m−1)=569.

Example 106-{6-[3-(6-tert-Butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-2-methyl-3-oxo-2,3-dihydro-pyridazin-4-ylamino}-N,N-dimethyl-nicotinamide

Step 4

In a 50 mL round-bottomed flask,6-(6-(3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-2-(hydroxymethyl)phenyl)-2-methyl-3-oxo-2,3-dihydropyridazin-4-ylamino)nicotinicacid (34 mg, 59.6 μmol, Eq: 1.00), dimethylamine 2M in THF (38.7 μA,77.5 μmol, Eq: 1.3) and Hunig's base (23.1 mg, 31.2 μl, 179 μmol, Eq: 3)were combined with DMF (1 ml) to give a yellow solution. HATU (27.2 mg,71.5 μmol, Eq: 1.2) was added and the reaction mixture was stirred at25° C. for 21 h. LC-MS at t=21 h showed the reaction was complete. Thereaction mixture was diluted with H₂O and DCM. The two phase mixture wasfiltered and the aqueous layer was back-extracted with DCM (3×20 mL).The organic layers were combined, washed with water, dried over Na₂SO₄and concentrated in vacuo to a peach colored solid. The crude materialwas purified by flash chromatography (silica gel, 25 g, 0% to 5% MeOH inDCM). The product was dried under vacuum to give 11 mg of a whitecrystalline solid in 31% yield. ¹H NMR in CDCl₃ is consistent withdesired product. MS (m+1)=598.

Preparation of I-11 Example 11

To a solution of 5-(trifluoromethyl)pyrazin-2-amine (146 mg, 0.90 mmol),4-bromo-6-chloro-2-methylpyridazin-3(2H)-one (200 mg, 0.90 mmol), cesiumcarbonate (1.02 g, 3.13 mmol) and4,5-bis(diphenylphosphino)-9,9-dimethylxanthine (77.7 mg, 0.13 mmol) indioxane (10.0 ml) was added tris(dibenzylideneacetone)dipalladium(0)(61.5 mg, 0.07 mmol) and the reaction mixture purged with argon (3×)before being warmed to 90° C. for 18 hr. The mixture was cooled, dilutedwith dichloromethane and water (50 mL) and the layers separated. Theaqueous phase was extracted with methylene chloride (2×25 mL). Theorganic phases were combined and dried over MgSO₄. The mixture wasfiltered and evaporated and the residue purified via automated flashchromatography (Analogix, SF15-24 g column, 1%-10%methanol/dichloromethane gradient) to give6-chloro-2-methyl-4-(5-trifluoromethyl-pyrazin-2-ylamino)-2H-pyridazin-3-one(197 mg, 72%) as a yellow solid: LC/MS m/e calculated for C₁₀H₇ClF₃N₅O[M]⁺305.03, observed 305.9

A solution of6-chloro-2-methyl-4-(5-(trifluoromethyl)pyrazin-2-ylamino)pyridazin-3(2H)-one(109 mg, 0.36 mmol),2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate (264 mg, 0.54 mmol), potassium phosphate (189 mg, 0.89 mmol) and2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (17.0 mg, 0.04mmol) in n-butanol (4 ml) and water (1 ml) was bubbled argon gas for 10min. To this solution was added bis(dibenzylideneacetone)dipalladium(0)(10.3 mg, 0.02 mmol) was added and the resulting mixture heated to 100°C. for 2 hr. The mixture was cooled and then poured into a saturatedammonium chloride solution. The resulting mixture was extracted withmethylene chloride (2×100 ml). The organic phases were combined anddried over MgSO₄. The mixture was filtered and evaporated and theresidue dissolved in dioxane (10 mL). To this solution was slowly addeda 2 M lithium hydroxide solution (0.5 mL) and the resulting mixturestirred at room temperature overnight. The resulting mixture was pouredinto a saturated ammonium chloride solution. The mixture was extractedwith methylene chloride (2×150 ml). The organic phases were combined anddried over MgSO₄. The mixture was filtered and evaporated and theresidue purified via automated flash chromatography (Analogix, SF15-24 gcolumn, 1%-10% methanol/dichloromethane gradient) to give a light yellowsolid which was recrystallized from methanol/dichloromethane to give6-tert-butyl-8-fluoro-2-{2-hydroxymethyl-3-[1-methyl-6-oxo-5-(5-trifluoromethyl-pyrazin-2-ylamino)-1,6-dihydro-pyridazin-3-yl]-phenyl}-2H-phthalazin-1-one(65 mg, 31%) as a white solid: Mp 250-254° C.; LC/MS m/e calculated forC₂₉H₂₅F₄N₇O₃ [M+H]⁺ 596.20, observed 596.3; ¹H NMR (DMSO-d₆) δ: 10.38(s, 1H), 8.71-9.08 (m, 2H), 8.43-8.66 (m, 2H), 7.68-8.02 (m, 2H),7.38-7.65 (m, 3H), 4.54-4.76 (m, 1H), 4.40 (br. s., 2H), 3.82 (s, 3H),1.38 (s, 9H).

This example illustrates the synthesis of“6-tert-butyl-8-fluoro-2-(3-{5-[5-(2-hydroxy-1,1-dimethyl-ethoxy)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-2-hydroxymethyl-phenyl)-2H-phthalazin-1-one”.

Step 1. Preparation of 2-(6-amino-pyridin-3-yloxy)-2-methyl-propionicacid ethyl ester

To a flask containing 6-aminopyridin-3-ol hydrobromide (2 g, 10.5 mmol)and ethyl-2-bromo-2-methylpropanate (2.04 g, 10.5 mmol) in anhydrousacetonitrile (25 ml) was added cesium carbonate (10.7 g, 33 mmol) andthe material was stirred for 16 hours under argon atmosphere. Water (60ml) and ethyl acetate (60 ml) were added and the material was shaken ina reparatory funnel. The organic phase was collected and the aqueousphase was back extracted with ethyl acetate (2×50 ml). The combinedorganic phases were dried over magnesium sulfate, filtered andconcentrated in vacuo. to provide a golden brown solid (1.626g)(M+H)⁺=225 m/e.

Step 2. Preparation of2-[6-(6-chloro-2-methyl-3-oxo-2,3-dihydro-pyridazin-4-ylamino)-pyridin-3-yloxy]-2-methyl-propionicacid ethyl ester

A flask containing 2-(6-amino-pyridin-3-yloxy)-2-methyl-propionic acidethyl ester (1.365 g, 6.09 mmol),4-bromo-6-chloro-2-methylpyridazin-3(2H)-one (1.77 g, 7.91 mmol),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (528 mg, 0.913 mmol) andcesium carbonate (6.94 g, 21.3 mmol) in dry dioxane (60 ml) wasevacuated under vacuum and back filled with argon (repeat 3 times).Tris(dibenzylideneacetone)dipalladium (0) (418 mg, 0.457 mmol) was addedand the flask evacuated under vacuum and back filled with argon (repeat3 times). The flask was place in an oil bath heated to 90° C. andstirred for 16 hours under argon atmosphere. The flask was cooled toambient and the material was filtered through a plug of celite, rinsingwell with dioxane. The volatiles were concentrated in vacuo. and theresidue was purified by silica gel chromatography, eluting with 5% to25% ethyl acetate/hexane to provide the desired product as a lightyellow-brown powder (2.035 g). (M+H)⁺=367 m/e.

Step 3. Preparation of6-chloro-4-[5-(2-hydroxy-1,1-dimethyl-ethoxy)-pyridin-2-ylamino]-2-methyl-2H-pyridazin-3-one

2-[6-(6-Chloro-2-methyl-3-oxo-2,3-dihydro-pyridazin-4-ylamino)-pyridin-3-yloxy]-2-methyl-propionicacid ethyl ester (1.23 g, 3.35 mmol, Eq: 1.00) was dissolved inanhydrous THF (25 ml) and cooled to −30° C. (dry ice/acetonitrilecooling bath) under nitrogen atmosphere A solution of lithium aluminumhydride (4.7 ml, 4.69 mmol, 1.0 M in THF) was added slowly, over 10minutes via drop-wise addition. The mixture was stirred for 1 hour whilemaintaining the bath temperature at about −20° C. The reaction wascarefully quenched by adding water (0.1 ml) and stirring for 10 minutesto ambient. Then a 5% aqueous solution of sodium hydroxide (0.19 ml) wasadded and the mixture stirred for 10 minutes. Water (0.19 ml) was addedand stirring continued for 10 minutes. Finally magnesium sulfate wasadded and the material was filtered through a plug of celite, rinsingwell with tetrahydrofuran. The material was concentrated on a rotaryevaporator to about half the volume. Ethyl acetate (50 ml) and water (70ml) was added and the material was shaken in a reparatory funnel. Theorganic phase was collected and the aqueous phase was back extractedwith ethyl acetate (2×40 ml). The organics were combined, dried withmagnesium sulfate, filtered and concentrated in vacuo. The residue wastriturated from hot dichloromethane/hexanes to provide the desiredproduct as a light yellow-brown solid (1.041 g). (M+H)⁺=325 m/e.

Step 4. Preparation of acetic acid2-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-6-{5-[5-(2-hydroxy-1,1-dimethyl-ethoxy)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-benzylester

This reaction was carried out under similar conditions to thosedescribed in step 7, example I-6, but substituting6-chloro-4-[5-(2-hydroxy-1,1-dimethyl-ethoxy)-pyridin-2-ylamino]-2-methyl-2H-pyridazin-3-onefor6-chloro-4-[5-(2-dimethylamino-1,1-dimethyl-ethoxy)-pyridin-2-ylamino]-2-methyl-2H-pyridazin-3-one.After work-up the product was purified by preparative thin layerchromatography (3 plates), eluting with 5% methanol/methylene chloride.This provided the desired product (together with some des-acetylproduct) as a light brown viscous oil (400 mg). (M+H)⁺=657 m/e.

Example 12 Step 5. Preparation of6-tert-butyl-8-fluoro-2-(3-{5-[5-(2-hydroxy-1,1-dimethyl-ethoxy)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-2-hydroxymethyl-phenyl)-2H-phthalazin-1-one

This reaction was carried out under similar conditions to thosedescribed in step 8, example I-6. After work-up the product was purifiedby preparative thin layer chromatography (3 plates), eluting with 2%methanol/methylene chloride. The plates were then re-developed with 3%and then 5% methanol/methylene chloride. This provided the desiredproduct as a light yellow solid (226 mg). (M+H)⁺=615 m/e. ¹H NMR (300MHz, CHLOROFORM-d) δ ppm 1.27 (s, 6H) 1.43 (s, 9H) 2.14 (t, J=6.42 Hz,1H) 3.61 (d, J=6.04 Hz, 2H) 3.90 (s, 3H) 3.91-3.95 (m, 1H) 4.42 (d,J=6.80 Hz, 2H) 6.92 (d, J=8.69 Hz, 1H) 7.32 (dd, J=8.88, 2.83 Hz, 1H)7.43-7.54 (m, 3H) 7.57 (t, J=7.90 Hz, 1H) 7.63-7.70 (m, 1H) 8.09 (d,J=3.02 Hz, 1H) 8.24-8.32 (m, 2H) 8.55 (s, 1H)

This example illustrates the synthesis of“2-(3-{5-[5-(2-Azetidin-1-yl-1,1-dimethyl-ethoxy)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-2-hydroxymethyl-phenyl)-6-tert-butyl-8-fluoro-2H-phthalazin-1-one”.

Step 1. Preparation of2-[6-(6-chloro-2-methyl-3-oxo-2,3-dihydro-pyridazin-4-ylamino)-pyridin-3-yloxy]-2-methyl-propionaldehyde

6-Chloro-4-(5-(1-hydroxy-2-methylpropan-2-yloxy)pyridine-2-ylamino)-2-methylpyridazin-3-(2H)-one(965 mg, 2.97 mmol) was taken up in a mixture of tetrahydrofuran (25 ml)and dichloromethane (15 ml). To the suspension was added Dess-MartinPeriodinane (1.64 g, 3.86 mmol) and the flask was capped and stirred for40 minutes. An aqueous saturated solution of sodium bicarbonate (50 ml)followed by the addition of an aqueous 10% solution of sodiumthiosulfate (50 ml) and the material was stirred vigorously for 15minutes. Ethyl acetate (50 ml) was added and the contents were shaken ina separatory funnel. The organic phase was collected and washed withbrine solution (50 ml). The ethyl acetate phase was collected and theaqueous phases were back extracted with dichloromethane (2×40 ml). Thecombined organic phases were dried over magnesium sulfate, filtered andconcentrated in vacuo. The product was purified via trituration from hotdichloromethane/hexanes to provide a brown solid (688 mg) (M+H)⁺=323m/e.

Step 2. Preparation of4-[5-(2-Azetidin-1-yl-1,1-dimethyl-ethoxy)-pyridin-2-ylamino]-6-chloro-2-methyl-2H-pyridazin-3-one

A pressure flask containing2-[6-(6-chloro-2-methyl-3-oxo-2,3-dihydro-pyridazin-4-ylamino)-pyridin-3-yloxy]-2-methyl-propionaldehyde(188 mg, 0.582 mmol) was taken up in dichloromethane (2.5 ml). Sodiumtriacetoxyborohydride (309 mg, 1.46 mmol) and acetic acid (0.1 ml, 1.75mmol) were added and the flask was next cooled in an ice bath undernitrogen atmosphere. Azetidine (0.24 ml, 3.49 mmol) was added and theflask was sealed. The flask was placed in an oil bath heated to 50° C.and stirred for 16 hours. The mixture was cooled to ambient and taken upin dichloromethane (50 ml) and a saturated solution of aqueous sodiumbicarbonate (50 ml). The material was transferred to a separatory funneland shaken. The organic phase was collected and washed with a solutionof 50% diluted brine (50 ml). The dichloromethane phase was collectedand the aqueous phases were back extracted with methylene chloride (2×40ml). The combined organic phase was dried (magnesium sulfate), filteredand concentrated in vacuo. The crude residue was loaded onto twopreparatory TLC plates and eluted with 8% methanol/dichloromethane. Theproduct band was collected to provide the desired product as a lightwhite-brown powder (139 mg). (M+H)⁺=364 m/e.

Step 3. Preparation of acetic acid2-{5-[5-(2-azetidin-1-yl-1,1-dimethyl-ethoxy)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-6-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-benzylester

Acetic acid2-{5-[5-(2-azetidin-1-yl-1,1-dimethyl-ethoxy)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-6-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-benzylester was prepared using the general procedure described in step 7 forthe preparation of I-6. After work up the material was purified bypreparative TLC (3 plates, eluting with 8% methanol/dichloromethane toprovide the desired product as a light brown viscous oil (238 mg).

(M+H)⁺=696 m/e.

Example 13 Step 4. Preparation of2-(3-{5-[5-(2-azetidin-1-yl-1,1-dimethyl-ethoxy)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-2-hydroxymethyl-phenyl)-6-tert-butyl-8-fluoro-2H-phthalazin-1-one

2-(3-{5-[5-(2-Azetidin-1-yl-1,1-dimethyl-ethoxy)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-2-hydroxymethyl-phenyl)-6-tert-butyl-8-fluoro-2H-phthalazin-1-onewas prepared using the general procedure described in step 8 of thepreparation of I-6. After work up the product was purified bypreparative TLC on silica gel, eluting with 3% methanol/methylenechloride and then re-developing with 5%, 8% and then finally 11%methanol/methylene chloride. This provided the desired product as alight brown powder (96 mg). (M+H)¹=654 m/e. ¹H NMR (300 MHz,CHLOROFORM-d) δ ppm 1.21 (s, 6H) 1.40 (s, 9 H) 2.11 (quin, J=7.20 Hz,2H) 2.58 (s, 2H) 3.35 (t, J=6.99 Hz, 4H) 3.87 (s, 3H) 4.40 (s, 2H) 6.90(d, J=9.06 Hz, 1H) 7.29 (dd, J=8.88, 2.83 Hz, 1H) 7.39-7.69 (m, 5H) 8.04(d, J=2.64 Hz, 1H) 8.27 (d, J=2.64 Hz, 1H) 8.32 (s, 1H) 8.51 (s, 1H).

This example illustrates the synthesis of“6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{5-[5-(2-hydroxy-2-methyl-propoxy)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one”.

Step 1. Preparation of I-(6-amino-pyridin-3-yloxy)-2-methyl-propan-2-ol

To a microwave flask containing 6-aminopyridin-3-ol hydrobromide (700mg, 3.66 mmol) and 1-chloro-2-methyl-2-propanol (597 mg, 5.5 mmol) inanhydrous dimethylformamide (17 ml) was added cesium carbonate (3.7 g,11.4 mmol) and the material was heated in a microwave oven at 140° C.for 3 hours. The vial was cooled to ambient and the solvent wasconcentrated in vacuo (rotary evaporator/mechanical pump). The residuewas taken up in methylene chloride and filtered to remove insolubles,rinsing well with methylene chloride. The crude material was purified byHPLC on silica gel, eluting with a gradient of 2% to 10%methanol/methylene chloride to provide the desired product as aorange-brown viscous oil which solidified on standing (449 mg). MS(H+)=183 m/e.

Step 2. Preparation of6-chloro-4-[5-(2-hydroxy-2-methyl-propoxy)-pyridin-2-ylamino]-2-methyl-2H-pyridazin-3-one

6-Chloro-4-[5-(2-hydroxy-2-methyl-propoxy)-pyridin-2-ylamino]-2-methyl-2H-pyridazin-3-onewas prepared using the general procedure described in step 6 of thepreparation of I-6. The crude product was purified by preparative thinlayer chromatography (3 plates), eluting with 4.5% methanol/methylenechloride to provide the desired product as a light yellow powder (392mg). (M+H)⁺=325 m/e.

Step 3. Preparation of acetic acid2-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-6-{5-[5-(2-hydroxy-2-methyl-propoxy)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-benzylester

This reaction was carried out under similar conditions to thosedescribed in step 7, example I-6, but substituting6-chloro-4-[5-(2-hydroxy-2-methyl-propoxy)-pyridin-2-ylamino]-2-methyl-2H-pyridazin-3-onefor6-chloro-4-[5-(2-dimethylamino-1,1-dimethyl-ethoxy)-pyridin-2-ylamino]-2-methyl-2H-pyridazin-3-one.After work-up the product was purified by preparative thin layerchromatography (2 plates), eluting with 5% methanol/methylene chloride.This provided the desired product (together with some des-acetylproduct) as a light yellow powder (284 mg).

(M+H)⁺=657 m/e.

Example 14 Step 4. Preparation of6-tert-butyl-8-fluoro-2-(2-hydroxymethyl-3-{5-[5-(2-hydroxy-2-methyl-propoxy)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one

This reaction was carried out under similar conditions to thosedescribed in step 8, example I-6. After work-up the product was purifiedby preparative thin layer chromatography (2 plates), eluting with 3.5%methanol/methylene chloride. The plates were then re-developed with 5%methanol/methylene chloride. This provided the desired product as alight yellow solid (195 mg). (M+H)⁺=615 m/e. ¹H NMR (300 MHz, DMSO-d₆) δppm 1.16 (s, 6H) 1.37 (s, 9H) 3.72 (s, 2H) 3.76 (s, 3H) 4.32-4.46 (m,2H) 4.51-4.59 (m, 1H) 4.61 (s, 1H) 7.39 (dd, J=8.69, 3.02 Hz, 1H)7.43-7.57 (m, 4H) 7.69-7.78 (m, 1H) 7.86 (br. s, 1H) 8.02 (d, J=2.64 Hz,1H) 8.39 (s, 1H) 8.50 (d, J=2.64 Hz, 1H) 9.31 (s, 1H).

This example illustrates the synthesis of“2-[8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-1-oxo-1,2-dihydro-isoquinolin-6-yl]-2-methyl-propionitrile”.

Step 1. Preparation of2,4,6-trifluoro-N-(2-hydroxy-1,1-dimethyl-ethyl)-benzamide

A flask, fitted with a calcium chloride drying tube, was charged with2,4,6-trifluorobenzoic acid (25 g, 142 mmol) and taken up in drydichloromethane (220 mL). The material was cooled to 0° C. (ice bath)and to this was added oxalyl chloride (13.2 ml; 156 mmol) via syringe.Dry dimethylformamide (104 mg; 1.42 mmol) was next added and moderatebubbling was observed. After 15 minutes the cooling bath was removed andthe mixture was stirred vigorously for 5 hours. The volatiles wereconcentrated in vacuo. (rotary evaporator) and the residue was taken upin dry dichloromethane (150 ml) and cooled to 0° C. (ice bath). To thissolution was added 2-amino-2-methyl-1-propanol (27.2 ml, 284 mmol) viaslow drop-wise addition. After complete addition the cooling bath wasremoved and the mixture was warmed to ambient over night.

The reaction, as described above was repeated on the same scale, and thecombined reaction products were worked up as follows: Thenon-homogeneous mixture was suction filtered, rinsing withdichloromethane (approximately 300 ml). This first filtrate was setaside and the solid was rinsed a second time with dichloromethane (500ml) using slow gravity filtration. The dichloromethane from the secondfiltration was concentrated in vacuo, which provided very pure productas a white crystalline solid (22.9 g). The dichloromethane solution fromthe first filtration was concentrated in vacuo to provide an impurebrown colored residue. This material was taken up in dichloromethane(200 ml) and water (250 ml) and shaken in a reparatory funnel. Theorganic phase was collected and the aqueous phase back extracted withdichloromethane (2×120 ml). The dichloromethane phases were combined,dried (magnesium sulfate), filtered and concentrated in vacuo. The cruderesidue was purified via trituration from hot dichloromethane/hexanes toprovide additional desired product as a yellow solid (43.8 g).

(M+H)⁺=246 m/e.

Step 2. Preparation of4,4-dimethyl-2-(2,4,6-trifluoro-phenyl)-4,5-dihydro-oxazole

To a solution of2,4,6-trifluoro-N-(2-hydroxy-1,1-dimethyl-ethyl)-benzamide (43.8 g,177.1 mmol) in dry dichloromethane (400 mL) was added thionyl chloride(58.9 ml, 415 mmol) via slow drop-wise addition over 25 minutes(reaction flask was immersed in an ice bath part way through theaddition to control the temperature). After complete addition thematerial was stirred at ambient temperature over night. The volume wasreduced to 30% by concentration under vacuum. To that was added ether(200 ml) and a solid precipitate (39.94 g off-white solid) was collectedby filtration. The ether filtrate was set aside and the solid materialwas taken up in water (120 ml) and treated with an aqueous solution ofsodium hydroxide (2N, 55 ml). Ethyl acetate (120 ml) was added and themixture was transferred to a separatory funnel and shaken. The organicphase was collected and washed with an equal volume of water. The ethylacetate phase was collected and the aqueous phases were back extractedwith ethyl acetate (2×100 ml). The combined organic phases were dried(magnesium sulfate), filtered and concentrated in vacuo to provide thedesired as a pure off-white solid (33.98 g). (M+H)⁺=230 m/e.

Step 3. Preparation of2-(2,4-difluoro-6-methyl-phenyl)-4,4-dimethyl-4,5-dihydro-oxazole

To a cooled (ice bath) solution of4,4-dimethyl-2-(2,4,6-trifluorophenyl)-4,5-dihydrooxazole (16.8 g, 73.3mmol) in dry tetrahydrofuran (150 ml) was added a solution of methylmagnesium bromide (73.3 ml, 3M in ether) via slow drop-wise addition.The mixture was stirred for 2 hours at 0° C. and then warmed to ambientover 6 hours. The reaction was carefully quenched via the addition asaturated aqueous solution of ammonium chloride (30 ml) and the materialwas taken up in water (200 ml) and ethyl acetate (150 ml), transferredto a separatory funnel and the organic phase was collected. The organicphase was washed with water (200 ml) and the ethyl acetate phasecollected. The aqueous phases were back extracted with ethyl acetate(2×120 ml) and the organic phases were combined, dried over magnesiumsulfate, filtered and concentrated in vacuo to provide the desiredproduct as a light yellow oil (16.31 g). (M+H)⁺=226 m/e.

Step 4. Preparation of2-[4-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)-3-fluoro-5-methyl-phenyl]-2-methyl-propionitrile

A flask containing a solution of2-(2,4-difluoro-6-methylphenyl)-4,4-dimethyl-4,5-dihydrooxazole (14.84g, 65.9 mmol) and isobutyronitrile (9.11 g, 132 mmol) in drytetrahydrofuran (130 ml) was cooled to −15 to −20° C. (acetonitrile/dryice bath) under an argon atmosphere. A solution of potassiumbis(trimethylsily) amide (171 ml, 0.5M in toluene) was added via slowdrop-wise addition. The mixture was stirred for 30 minutes at −15° C.and then gradually warmed to 15° C. over about 1.5 hours. The materialwas quenched via the addition of a saturated solution of aqueousammonium chloride (100 ml). Water (80 ml) and diethyl ether (50 ml) wereadded and the material was transferred to a reparatory funnel and theorganic phase was collected. This was washed with an equal volume ofwater and the organic phase was collected. The aqueous phases were backextracted with ether (2×100 ml) and the combined organic phases weredried over magnesium sulfate, filtered and concentrated in vacuo. Thematerial was purified by chromatography on silica gel eluting with 60%ethyl acetate/hexane to provide semi-pure product as a golden yellow oil(18 g, 75% pure). This material was used “as is” in subsequent steps.(M+H)⁺=275 m/e.

Step 5. Preparation of2-(4-(2-cyanoporopyl-2-yl)-2-fluoro-6-methylphenyl)-3,4,4-trimethyl-4,5-dihydrooxazole-3-iumiodide

To a solution2-[4-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)-3-fluoro-5-methyl-phenyl]-2-methyl-propionitrile(23.86 g, 60% purity, 52.2 mmol) in dry acetonitrile (237 ml) was addedmethyl iodide (37 g, 261 mmol) via drop-wise addition over 10 minutes.The mixture was transferred to an oil bath heated to 63° C. and stirredover night. The flask was cooled to ambient and then in an ice bath anda solid precipitated product was collected by decantation, providing thedesired product as an off-white solid which turned light yellow onstanding (21.9 g). Material was used “as is” in the next step.

Step 6. Preparation of4-(cyano-dimethyl-methyl)-2-fluoro-6-methyl-benzoic acid

A flask was charged with2-(4-(2-cyanopropyl-2-yl)-2-fluoro-6-methylphenyl)-3,4,4-trimethyl-4,5-dihydrooxazole-3-iumiodide (21.9 g, 52.7 mmol) and methanol (89 ml). To this slurry wasadded a solution of sodium hydroxide (10.5 g, 263 mmol) in water (178ml) and the material was heated in an oil bath at 80° C. The mixture wasvigorously stirred for 60 minutes and then toluene (120 ml) was added.The mixture was stirred and shaken for 5 minutes in the oil bath. Whilestill hot the material was transferred to a separatory funnel and theaqueous phase was collected. This was acidified with aqueous 1.5 Nhydrochloric acid (to pH=1). Ethyl acetate (25 ml) and water (5 ml) areadded and the mixture was shaken in a separatory funnel. The organicphase was collected and the aqueous phase was back extracted with ethylacetate (2×40 ml). The combined organic phases were dried with magnesiumsulfate, filtered and concentrated in vacuo to provide semi-pure productas a light yellow solid (5.4 g). (M−H)-=220 m/e.

Step 7. Preparation of4-(cyano-dimethyl-methyl)-2-fluoro-6-methyl-benzamide

4-(2-cyanopropan-2-yl)-2-fluoro-6-methylbenzoic acid (14 g, 35 mmol, 75%pure) was taken up in dry tetrahydrofuran (100 ml). To this was added1,1′-carbonyldiimidazole (11.2 g, 69.1 mmol) in four equal portions over15 minutes. The mixture was stirred for 2.5 hours and then a 28% aqueoussolution of ammonium hydroxide (20.4 ml) was added via drop-wiseaddition. The material was stirred for 4 hours and then concentratedunder reduced pressure to remove 90% of the volatiles. The residue wastaken up in water (80 ml) and dichloromethane (80 ml) and shaken in areparatory funnel. The organic phase was collected and the aqueous phasewas back extracted with dichloromethane (3×60 ml). The combined organicphase was dried (magnesium sulfate), filtered and concentrated in vacuoand the resultant semisolid was purified via trituration from hotdichloromethane/hexanes to provide the desired product as aslightly-impure off-white solid (10.71 g, 80% purity). (M+H)⁺=221 m/e.

Step 8. Preparation4-(cyano-dimethyl-methyl)-N-[1-dimethylamino-meth-(E)-ylidene]-2-fluoro-6-methyl-benzamide

In a 250 ml round bottom flask was placed4-(2-cyanopropan-2-yl)-2-fluoro-6-methylbenzamide (8.71 g, 31.6 mmol,80% purity) and dimethylformamide dimethylacetal (7.26 ml, 51.4 mmol) intetrahydrofuran (61 ml) to provide a non-homogeneous yellow suspension.The reaction mixture was heated to 63° C. (oil bath) and stirred for 3hours. The mixture was concentrated on the rotary evaporator and thentaken up in hexane (80 ml). This mixture was stirred vigorously for afew minutes until a white precipitate forms. The product was collectedby filtration, rinsing well with hexane to provide product as a whitesolid (7.02 g). (M+H)⁺=276 m/e.

Step 9. Preparation of2-(8-fluoro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-methyl-propionitrile

4-(Cyano-dimethyl-methyl)-N-[1-dimethylamino-meth-(E)-ylidene]-2-fluoro-6-methyl-benzamide.(10.66 g, 38.7 mmol) was taken up in dry tetrahydrofuran (100 ml) andplaced in an oil bath heated to 55° C. A solution of potassiumtert-butoxide (58.1 ml, 1M in tetrahydrofuran) was added drop-wise froman addition funnel over 15 minutes. The reaction mixture was heated to62° C. and stirred for 2 hours. The resultant thick suspension wascooled to ambient and treated with concentrated hydrochloric acid (5.3ml) via drop-wise addition. Water (30 ml) was added and the material wastransferred to a separatory funnel. The organic phase was collected andwashed with brine solution (25 ml). The aqueous phase was back extractedwith ethyl acetate (25 ml) and the organics are combined, dried withmagnesium sulfate, filtered and concentrated in vacuo. The residue wascrystallized from hot dichloromethane/hexanes to provide the desiredproduct as an off-white solid (5.91 g). (M+H)⁺=231 m/e.

Step 10. Preparation of242-(3-bromo-2-formyl-phenyl)-8-fluoro-1-oxo-1,2-dihydro-isoquinolin-6-yl]-2-methyl-propionitrile

A solution of2-(8-fluoro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-methyl-propionitrile(250 mg, 1.09 mmol), 2,6-dibromobenzaldehyde (459 mg, 1.74 mmol) andsodium bicarbonate (182 mg, 2.17 mmol) in dry dimethylsulfoxide (8 ml)was placed under vacuum and back-filled with argon (repeat twice more).To this was added copper iodide (207 mg, 1.09 mmol) and the flask wasevacuated and back-filled with argon (repeat twice more). The mixturewas heated in an oil bath to 110° C. and stirred for 3.5 hours. Thereaction mixture was cooled to ambient and taken up in ethyl acetate (40ml) and water (40 ml). The biphasic material was filtered through a plugof celite, rinsing well with ethyl acetate. The filtrate and washes weretransferred to a separatory funnel and the organic phase was collected.This was washed with an equal volume of 50% diluted brine solution andthe ethyl acetate phase collected. The aqueous phases were backextracted with ethyl acetate (2×30 ml). The combined organic phase wasdried with magnesium sulfate, filtered and concentrated in vacuo. Theresidue was purified by HPLC on silica gel, eluting with 1%methanol/dichloromethane to provide the desired product as a lightyellow solid (285 mg). (M+H)⁺=413/415 m/e.

Step 11. Preparation of2-[8-fluoro-2-(2-formyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-1-oxo-1,2-dihydro-isoquinolin-6-yl]-2-methyl-propionitrile

6-chloro-2-methyl-4-(5-morpholine-4-carbonyl)pyridine-2-ylamino)pyridazin-3(2H)-one(143 mg, 0.41 mmol), bis(pinacolato)diboron (135 mg, 0.53 mmol),2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (x-phos, 29 mg,0.061 mmol) and potassium acetate (120 mg, 1.23 mmol) were taken up indry dioxane (6.4 ml) and placed under vacuum and back-filled with argon(repeat five times). To this was added palladium acetate (10 mg, 0.045mmol) and the flask was evacuated and back-filled with argon (repeatfive times). The mixture was heated in an oil bath to 100° C. andstirred for 16 minutes. The flask was cooled to ambient and the crudecontents of this flask were filtered (through celite, rinse through with3 ml dioxane) into a second flask (immersed in a 110° C. oil bath underargon balloon) which contained a vacuum de-gassed solution of thefollowing reagents:2-(2-(3-bromo-2-formylphenyl)-8-fluoro-1-oxo-1,2-dihydroisoquinolin-6-yl)-2-methylpropanenitrile(169 mg, 0.41 mmol), potassium carbonate (283 mg, 2.04 mmol),tricyclohexylphosphine (35.1 mg, 0.125 mmol) andbis(dibenzylideneacetone)palladium (35 mg, 0.061 mmol) in a mixture ofn-butanol (0.5 ml), dioxane (2.1 ml) and water (2 ml). The flask wasstirred and heated for 1 hour and then cooled to ambient. The crudereaction mixture was filtered through a short plug of celite, rinsingwell with ethyl acetate. To the combined filtrate and washes was addedwater (30 ml) and the material was shaken in a separatory funnel. Theorganic phase was collected and the aqueous phase was back extractedwith ethyl acetate (2×20 ml). The combined organic phase was dried withsodium sulfate, filtered and concentrated in vacuo. The residue waspurified by HPLC on silica gel, eluting with 1% to 9%methanol/dichloromethane to provide the desired product as a lightyellow solid (224 mg). (M−H)⁻=646 m/e.

Example 15 Step 12. Preparation of2-[8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-1-oxo-1,2-dihydro-isoquinolin-6-yl]-2-methyl-propionitrile

A solution of2-[8-fluoro-2-(2-formyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-1-oxo-1,2-dihydro-isoquinolin-6-yl]-2-methyl-propionitrile(224 mg, 0.35 mmol) in methanol (2.8 ml) and dichloromethane (4.3 ml)was cooled in an ice bath. To this was added a solution of sodiumborohydride (65 mg, 1.7 mmol) in water (0.75 ml), via slow drop-wiseaddition. The mixture was stirred for 10 minutes and additional sodiumborohydride (as describe above was added twice more over 20 minutes. Theaqueous upper phase was carefully removed from the biphasic reactionsolution. Methanol (1 ml) was added and with rapid stirring 3 moreadditions of aqueous sodium borohydride were made (as described above)over about 25 minutes. Water (60 ml) and dichloromethane (60 ml) wereadded and the material was transferred to a separatory funnel and theorganic phase was collected. This was washed with an equal volume of 50%diluted brine solution and the dichloromethane phase collected. Theaqueous phases were back extracted with dichloromethane (2×40 ml). Thecombined organic phase was dried with magnesium sulfate, filtered andconcentrated in vacuo. The residue was purified by HPLC on silica gel,eluting with 1% to 8% methanol/dichloromethane to provide the desiredproduct which was further purified by crystallization from hotdichloromethane/hexane to provide desired product as a white solid (120mg). (M+H)⁺=650 m/e. ¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.81 (s, 6H)3.53-3.81 (m, 8H) 3.83-3.91 (m, 1H) 3.92 (s, 3H) 4.26-4.45 (m, 2H) 6.62(dd, J=7.55, 1.89 Hz, 1H) 7.00 (d, J=8.31 Hz, 1H) 7.22 (dd, J=12.46,1.89 Hz, 1H) 7.33 (d, J=7.18 Hz, 1H) 7.42 (dd, J=7.93, 1.51 Hz, 1H) 7.53(d, J=1.89 Hz, 1H) 7.57 (t, J=7.93 Hz, 1H) 7.65-7.70 (m, 1H) 7.78 (dd,J=8.69, 2.27 Hz, 1H) 8.41-8.47 (m, 2H) 8.70 (s, 1H).

This example illustrates the synthesis of“6-tert-Butyl-8-fluoro-2-(3-{5-[5-((S)-2-hydroxy-3-methoxy-propoxy)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-2-hydroxymethyl-phenyl)-2H-phthalazin-1-one”.

Step 1. Preparation of 2-Chloro-5-((S)-1-oxiranylmethoxy)-pyridine

In a 250 mL round-bottomed flask, 6-chloropyridin-3-ol (2.116 g, 16.3mmol), triphenylphosphine (5.14 g, 19.6 mmol) and(R)-oxiran-2-ylmethanol (1.21 g, 1.08 ml, 16.3 mmol) were combined withTHF (75.0 ml) to give a colorless solution. Cooled to 0° C. DEAD (3.41g, 3.1 ml, 19.6 mmol) was added. The reaction mixture was allowed tocome to 25° C. and stirred for 30 h. The reaction mixture wasconcentrated in vacuo. The crude product was purified by flashchromatography (silica gel, 80 g, 5% to 25% EtOAc in hexanes) followedby flash chromatography (silica gel, 40 g, 0.5% to 1% MeOH in DCM) toafford the desired product (1.8 g, 59%) as a white solid. (M+H)⁺=186m/e.

Step 2. Preparation of(S)-1-(6-Chloro-pyridin-3-yloxy)-3-methoxy-propan-2-ol

In a 125 mL round-bottomed flask,(S)-2-chloro-5-(oxiran-2-ylmethoxy)pyridine (1.8 g, 9.7 mmol) wascombined with MeOH (5.88 ml) to give a colorless solution. Cooled to 0°C. Boron trifluoride etherate (138 mg, 123 μA, 970 μmol) was added.Allowed to warm to RT. The reaction mixture was stirred at roomtemperature for overnight. The crude reaction mixture was concentratedin vacuo. The crude material was purified by flash chromatography(silica gel, 80 g, 0% to 60% EtOAc in hexanes) to yield the desiredproduct (1.37 g, 68%) as an oil. (M+H)⁺=218 m/e.

Step 3. Preparation of5-[(S)-2-(tert-Butyl-dimethyl-silanyloxy)-3-methoxy-propoxy]-pyridin-2-ylamine

(S)-1-(6-chloropyridin-3-yloxy)-3-methoxypropan-2-ol (1.37 g, 6.29 mmol)and imidazole (857 mg, 12.6 mmol) were combined in DMF (20 ml). DMAP(115 mg, 944 μmol) was added followed by TBDMS-Cl (1.23 g, 8.18 mmol)The reaction was stirred at 25° C. overnight. The reaction mixture waspoured into 150 mL H₂O and extracted with diethyl ether (4×100 mL).

The organic extracts were washed with brine, dried over MgSO₄ andconcentrated in vacuo. The crude material was purified by flashchromatography (silica gel, 40 g, 0% to 15% EtOAc in hexanes) to afford1.81 g of(S)-5-(2-(tert-butyldimethylsilyloxy)-3-methoxypropoxy)-2-chloropyridine(5.4 mmol), which was dissolved in 14 mL of THF in a sealed tube. Tothat was added 2-(dicyclohexylphosphino)biphenyl (380 mg, 1.08 mmol) togive a light yellow solution. This solution was degassed with argon.Tris(dibenzylideneacetone)dipalladium(0) (497 mg, 542 mmol) was addedfollowed by LiHMDS (16.3 ml of 1M solution in THF, 16.3 mmol). Thereaction was placed under an argon atmosphere and was sealed. Thereaction mixture was heated to 90° C. and stirred for 15 h. The reactionwas complete by LCMS. The mixture was cooled and diluted with EtOAc. Thereaction mixture was poured into 150 mL sat. NH₄Cl and extracted withEtOAc (4×75 mL). The organic layers were dried over MgSO₄ andconcentrated in vacuo. The crude material was purified by flashchromatography with stepwise gradient (silica gel, 80 g, 20% to 70%EtOAc in hexanes) to afford the desired product (1.09 g). (M+H)⁺=313m/e.

Step 4. Preparation of4-{5-[(S)-2-(tert-Butyl-dimethyl-silanyloxy)-3-methoxy-propoxy]-pyridin-2-ylamino}-6-chloro-2-methyl-2H-pyridazin-3-one

In a 50 mL round-bottomed flask,(S)-5-(2-(tert-butyldimethylsilyloxy)-3-methoxypropoxy)-pyridin-2-amine(340 mg, 1.09 mmol), 4-bromo-6-chloro-2-methylpyridazin-3(2H)-one (292mg, 1.31 mmol) and cesium carbonate (1.06 g, 3.26 mmol) were combined indioxane (25 ml) to give an orange suspension.4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (94.4 mg, 163 μmol) wasadded followed by tris(dibenzylideneacetone)dipalladium(0) (49.8 mg,54.4 μmol). The reaction solution was degassed with argon for 10 min.and warmed at 95-105° C. for 48 h.

The resultant reaction mixture was diluted with 200 ml DCM. MgSO₄ wasadded. The suspension was filtered and washed several times with DCM.The combined filtrate and washes were concentrated in vacuo. The crudematerial was purified by flash chromatography (silica gel, 40 g, 10% to25% EtOAc in hexanes) to afford the desired product (451 mg, 91%) as awhite solid. (M+H)⁺=455 m/e.

Step 5. Preparation of6-tert-Butyl-2-[3-(5-{5-[(S)-2-(tert-butyl-dimethyl-silanyloxy)-3-methoxy-propoxy]-pyridin-2-ylamino}-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl)-2-hydroxymethylphenyl]-8-fluoro-2H-phthalazin-1-one

In a 50 mL test tube,(S)-4-(5-(2-(tert-butyldimethylsilyloxy)-3-methoxypropoxy)pyridin-2-ylamino)-6-chloro-2-methylpyridazin-3(2H)-one(178 mg, 391 μmol) and2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate (332 mg, 469 μmol) were combined in n-butanol (4 ml) to give aorange solution. 1 mL of water was added and the reaction mixture waspurged with argon. X-PHOS (18.6 mg, 39.1 μmol) and potassium phosphatetribasic (166 mg, 782 μmol) were added. After argon was bubbled throughthe reaction mixture for 5 min. bis(dibenzylideneacetone)-palladium (0)(11.2 mg, 19.6 μmol) was added. The resulting suspension was heated in aoil bath at 110° C. for 1.5 hours. No(S)-4-(5-(2-(tert-butyldimethylsilyloxy)-3-methoxypropoxy)-pyridin-2-ylamino)-6-chloro-2-methylpyridazin-3(2H)-oneremained by LCMS. Two main products were observed by LCMS, acetylatedand deacetylated product. The reaction mixture was allowed to cool to25° C. overnight. The reaction mixture was concentrated to small volume,poured into 75 mL H₂O and extracted with EtOAc (3×75 mL). The organiclayers were dried over Na₂SO4 and concentrated in vacuo. The crudematerial was purified by flash chromatography (silica gel, 24 g, 20% to60% EtOAc in hexanes) to afford 2 product peaks. These were combined andconc. to give 290 mg of a 1:1 mixture of acetylated and deacetylatedproduct. This mixture was taken up in 15 mL THF and treated with 2 mL of1N NaOH. The reaction mixture was heated to 60° C. and stirred for 20 h.Mostly complete by tlc. The reaction mixture was poured into 100 mL H₂Oand extracted with EtOAc (3×50 mL). The combined organic extracts werewashed with brine, dried over MgSO₄ and concentrated in vacuo. The crudematerial was purified by flash chromatography (silica gel, 40 g, 20% to70% EtOAc in hexanes) to afford 217 mg of the desired product (75%yield). (M+H)⁺=745 m/e.

Example 16 Step 6. Preparation of6-tert-Butyl-8-fluoro-2-(3-{5-[5-((S)-2-hydroxy-3-methoxy-propoxy)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-2-hydroxymethyl-phenyl)-2H-phthalazin-1-one

In a 100 mL round-bottomed flask,(S)-6-tert-butyl-2-(3-(5-(5-(2-(tert-butyldimethylsilyloxy)-3-methoxypropoxy)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-(hydroxymethyl)phenyl)-8-fluorophthalazin-1(2H)-one(214 mg, 287 mmol, Eq: 1.00) was combined with THF (6.0 ml) to give ayellow solution. TBAF (500 μl of a 1M solution in THF, 500 μmol) wasadded and the resultant solution was stirred at 25° C. for 1 h. Thereaction was complete by LCMS. The reaction mixture was poured into 75mL H₂O and extracted with EtOAc (1×75 mL). An emulsion resulted.Saturated NaCl was added and the EtOAc layer was separated. Extracted 2times with DCM. No product left in aqueous phase by LCMS. The organiclayers were combined, dried over MgSO₄ and concentrated in vacuo. Thecrude material was purified by flash chromatography (silica gel, 24 g,0.5% to 4% MeOH in DCM) to afford a glass. The glass was taken up inEtOAc/hexane and conc. to give a semisolid, which was triturated withether. The resulting white solid was washed with ether/hexanes to give112 mg of pure product as a white powder. (M+H)⁺=631 m/e. ¹H NMR (300MHz, CHLOROFORM-d) δ ppm 1.44 (s, 9H) 3.44 (s, 3H) 3.53-3.64 (m, 2H)3.91 (s, 3H) 4.03-4.11 (m, 2H) 4.13-4.22 (m, 1H) 4.42 (s, 2H) 6.98 (d,J=8.69 Hz, 1H) 7.28-7.35 (m, 1H) 7.43-7.62 (m, 4H) 7.64-7.69 (m, 1H)8.06 (d, J=3.02 Hz, 1H) 8.27-8.32 (m, 2H) 8.48 (s, 1H)

Example 17 Preparation of6-tert-Butyl-8-fluoro-2-(3-{5-[5-(R)-2-hydroxy-3-methoxy-propoxy)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-2-hydroxymethyl-phenyl)-2H-phthalazin-1-one

Preparation by a similar procedure to Example 16, except substituting(S)-oxiran-2-ylmethanol for (R)-oxiran-2-ylmethanol in step 1, affordedthe desired product as a white powder (107 mg) (M+H)⁺=631 m/e. ¹H NMR(400 MHz, CHLOROFORM-d) δ ppm 1.44 (s, 9H) 3.44 (s, 3H) 3.53-3.63 (m,2H) 3.91 (s, 3H) 4.02-4.12 (m, 2H) 4.14-4.22 (m, 1H) 4.42 (s, 2H) 6.99(d, J=8.78 Hz, 1H) 7.32 (dd, J=9.03, 3.01 Hz, 1H) 7.45-7.61 (m, 4H)7.64-7.69 (m, 1H) 8.06 (d, J=2.76 Hz, 1H) 8.29 (d, J=2.51 Hz, 1H) 8.32(s, 1H) 8.47 (s, 1H)

This example illustrates the synthesis of“6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-((S)-1-methyl-pyrrolidin-2-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one”.

Step 1. Preparation of2-Chloro-5-((S)-1-methyl-pyrrolidin-2-yl)-pyridine

A 100 mL RB flask was placed under an argon atmosphere and degassed withargon by vacuum. The solvents (hexanes (4 ml) and toluene 12 ml)) wereadded to the flask. N,N-dimethylethanolamine (1.07 g, 1.21 ml, 12.0mmol) was added. The reaction mixture was cooled to 0° C. N-butyllithium (8.66 ml of 2.5M in hexanes, 21.6 mmol) was added. The reactionmixture was stirred at 0° C. for 30 min. The reaction mixture was cooledto −20° C. (S)-3-(1-methylpyrrolidin-2-yl)pyridine (650 mg, 0.64 ml,4.01 mmol) was added. The reaction mixture was stirred −20° C. for 1 h.The reaction mixture was cooled to −78° C. and hexachloroethane (3.8 g,16.0 mmol) was added in toluene (8 ml). The reaction mixture was stirredat −78° C. for 1 h. The reaction was quenched cold with satd. NaHCO₃ (4mL). LCMS showed that the reaction gave the desired regioisomer in a 6:1ratio over the undesired 6-chloro pyridine product. The reaction mixturewas poured into 50 mL H₂O and extracted with DCM (3×125 mL). The organiclayers were dried over Na₂SO₄ and concentrated in vacuo. The crudematerial was purified by flash chromatography (silica gel, 40 g, 0% to55% EtOAc in hexanes) to afford the desired product (467 mg, 59%). ¹HNMR (300 MHz, CHLOROFORM-d) δ ppm 1.56-2.05 (m, 3H) 2.16-2.40 (m andoverlapping s, 5H) 3.09 (t, J=8.31 Hz, 1H) 3.17-3.29 (m, 1H) 7.23-7.32(m, 1H) 7.68 (dd, J=8.12, 2.45 Hz, 1H) 8.30 (d, J=2.27 Hz, 1H)

Step 2. Preparation of5-((S)-1-Methyl-pyrrolidin-2-yl)-pyridin-2-ylamine

In a 75 mL sealed tube, (S)-2-chloro-5-(1-methylpyrrolidin-2-yl)pyridine(622 mg, 3.16 mmol) and 2-(dicyclohexylphosphino)biphenyl (222 mg, 633μmol) were combined with THF (15 ml) to give a light yellow solution.The solution was degassed with argon.Tris(dibenzylideneacetone)dipalladium (0) (290 mg, 316 μmol) was added.LiHMDS (9.49 ml of 1M solution in THF, 9.49 mmol) was added. Thereaction was placed under an argon atmosphere and sealed. The reactionmixture was heated to 90° C. and stirred for 15 h. Reaction was completeby tlc. The reaction mixture was cooled to room temperature and dilutedwith EtOAc. The reaction mixture was poured into 150 mL sat NH₄Cl andextracted with EtOAc (4×75 mL). The organic layers were dried over MgSO₄and concentrated in vacuo. The crude material was purified by flashchromatography with stepwise gradient (silica gel, 40 g, 10% to 50%(60:10:1 CH₂Cl₂:methanol: NH₄OH)/CH₂Cl₂) gradient to afford the desiredproduct (560 mg, 99%). ¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.57-2.03(m, 3H) 2.04-2.39 (m and overlapping s, 5H) 2.92 (t, J=8.12 Hz, 1H)3.14-3.29 (m, 1H) 4.40 (br. s., 2H) 6.51 (d, J=8.69 Hz, 1H) 7.47 (dd,J=8.31, 2.27 Hz, 1H) 7.95 (d, J=2.27 Hz, 1H)

Step 3. Preparation of6-Chloro-2-methyl-4-[5-((S)-1-methyl-pyrrolidin-2-yl)-pyridin-2-ylamino]-2H-pyridazin-3-one

In a 50 mL round-bottomed flask,5-((S)-1-methyl-pyrrolidin-2-yl)-pyridin-2-ylamine (560 mg, 3.16 mmol)],4-bromo-6-chloro-2-methylpyridazin-3(2H)-one (847 mg, 3.79 mmol) andcesium carbonate (3.09 g, 9.48 mmol) were combined with dioxane (25 ml)to give a orange suspension.4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (274 mg, 474 μmol, Eq:0.15) was added followed by tris(dibenzylideneacetone)dipalladium(0)(145 mg, 158 μmol, Eq: 0.05). The reaction was degassed with Ar for 10min and heated at 95-105° C. for 4 h. No aniline starting material wasleft. The reaction mixture was diluted with 200 ml DCM. MgSO4 was addedand stirred. The reaction was filtered and the filtercake was washedseveral times with DCM. The combined filtrate and washes wereconcentrated in vacuo. The crude material was purified by flashchromatography (silica gel, 40 g, 1% to 2% MeOH in DCM) to afford thedesired product (522 mg, 52%). (M+H)⁺=320 m/e.

Example 18 Step 4. Preparation of6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-((S)-1-methyl-pyrrolidin-2-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one

In a 50 mL RB flask,(S)-6-chloro-2-methyl-4-(5-(1-methylpyrrolidin-2-yl)pyridin-2-ylamino)pyridazin-3(2H)-one(125 mg, 0.39 mmol) and2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate (331 mg, 468 μmol) were combined with BuOH (4 ml) to give aorange solution. 1 mL of water was added. Purged with argon. X-PHOS(18.6 mg, 39.0 μmol) and potassium phosphate tribasic (166 mg, 780 μmol,were added. Argon was bubbled through for 10 min.Bis(dibenzylideneacetone)-palladium (0) (11.2 mg, 19.5 μmol) was added.The resultant reaction mixture was purged with argon and warmed in a oilbath at 110° C. for 1.5 hours. Two main products were observed by LCMS,acetylated and deacetylated product. The reaction was allowed to cool toRT overnight and then was concentrated to small volume. The reactionmixture was poured into 75 mL H₂O and extracted with EtOAc (3×75 mL).The organic layers were washed with brine and dried over MgSO4 andconcentrated in vacuo. The crude material was purified by flashchromatography (silica gel, 24 g, 1% to 5% MeOH in DCM) to afford 2peaks. The two peaks were combined and concentrated to give 238 mg of a1:1 mixture of acetylated and deacetylated product. This mixture wastaken up in 15 mL THF and treated with 2 mL of 1N NaOH. The reactionmixture was heated to 60° C. and stirred for 25 h. The reaction wasalmost complete by tlc. The reaction mixture was poured into 100 mL H₂Oand extracted with EtOAc (2×50 mL) and DCM (1×). No product remained inthe aqueous phase. The combined organic extracts were washed with brine,dried over MgSO4 and concentrated in vacuo. The crude material waspurified by flash chromatography (silica gel, 24 g, 1% to 5% MeOH inDCM) two times, followed by trituration with ethyl acetate/hexanes toafford 57 mg pure product. (M+H)⁺=610 m/e.

Example 19 Preparation of6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-((R)-1-methyl-pyrrolidin-2-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one

Preparation by a similar procedure to Example 18, except substituting(R)-3-(1-methylpyrrolidin-2-yl)pyridine for(S)-3-(1-methylpyrrolidin-2-yl)pyridine in step 1, afforded the desiredproduct as a white powder (78 mg). (M+H)⁺=610 m/e.

Preparation of I-20 Step 1. Preparation of6-Azido-N,N-dimethyl-nicotinamide

In a 500 mL round-bottomed flask, 6-chloro-N,N-dimethylnicotinamide(8.15 g, 44.1 mmol) was combined with DMF (50.0 ml) to give a brownsolution. Sodium azide (3.44 g, 53.0 mmol) was added and the reactionmixture was heated to 120° C. and stirred for 60 h. The reaction mixturewas diluted with 100 mL H₂O and extracted with EtOAc (2×200 mL). Theorganic layers were combined, washed with H₂O (1×50 mL), sat NaCl (1×100mL), dried over Na₂SO₄ and concentrated in vacuo to a yellow oil. MeOHwas added and the entire mixture solidified upon concentration. Thecrude product was dried under vacuum overnight. The pasty solid wasrecrystallized from EtOAc/Hex. The solid was filtered and washed with aminimal amount of hexane. The white powder was dried under vacuum at 45°C. for 3 hrs to give 2.23 g (26%) of the title compound. ¹H NMR (300MHz, CHLOROFORM-d) δ: 8.95 (s, 1H), 8.09 (d, J=9.1 Hz, 1H), 7.75 (dd,J=9.1, 1.5 Hz, 1H), 3.15 (br. s., 6H).

Step 2. Preparation of 6-Amino-N,N-dimethyl-nicotinamide

In a 250 mL round-bottomed flask, 6-azido-N,N-dimethylnicotinamide (2.26g, 11.8 mmol) was combined with ethyl acetate (50 ml) and methanol (30ml) to give a yellow solution. 10% Pd/C (200 mg, 1.88 mmol) was addedand the reaction mixture was evacuated and filled with H₂ twice. Thereaction mixture was stirred under balloon pressure of H₂ at 25° C. for17 h. The reaction mixture was filtered through celite and the filtercake was washed with MeOH. The filtrate was concentrated in vacuo andthe cream colored solid was dried under vacuum at 45° C. for 3 hrs togive the title compound in quantitative yield. (M+H)⁺=166 m/e. ¹H NMR(300 MHz, CHLOROFORM-d) δ: 8.21 (d, J=2.3 Hz, 1H), 7.59 (dd, J=8.3, 2.3Hz, 1H), 6.50 (d, J=8.7 Hz, 1H), 4.69 (br. s., 2H), 3.08 (s, 6H).

Step 3. Preparation of Acetic acid2-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-6-[5-(5-dimethylcarbamoyl-pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl]-benzylester

In a 250 mL round-bottomed flask,6-(6-chloro-2-methyl-3-oxo-2,3-dihydropyridazin-4-ylamino)-N,N-dimethylnicotinamide(1.053 g, 3.42 mmol),2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate (2.2 g, 4.45 mmol) and Cs₂CO₃ (3.34 g, 10.3 mmol) were combinedwith dioxane (20 ml) and water (2.00 ml) to give a dark brownsuspension. The suspension was purged with argon and PdCl₂(DPPF) (83.8mg, 10.3 mmol) was added. The reaction mixture was heated to 85° C. andstirred for 3 h. Cooled to 25° C. and diluted with DCM. Na₂SO₄ was addedand the mixture was filtered through celite. The filter cake was washedwith DCM until clear and the brown filtrate was conc. in vacuo. Thecrude material was purified by flash chromatography (silica gel, 220 g,0% to 5% MeOH in DCM). The product was isolated impure and repurified byflash chromatography (silica gel, 220 g, 100% EtOAc) to afford 1.1412 g(52%) of the title compound as a cream colored solid. (M+H)⁺=640 m/e.

Example 20 Step 4. Preparation of6-{6-[3-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-O-2-hydroxymethyl-phenyl]-2-methyl-3-oxo-2,3-dihydropyridazin-4-ylamino}-N,N-dimethylnicotinamide

In a 500 mL round-bottomed flask,2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(5-(5-(dimethylcarbamoyl)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)benzylacetate (1.142 g, 1.79 mmol) was combined with dioxane (25 ml) and 1MLiOH (10 ml) to give a light yellow suspension. The reaction mixture wasstirred at 25° C. for 17 h. The crude reaction mixture was concentratedin vacuo. The residue was partitioned between DCM and water. An emulsionwas obtained and the aqueous was extracted exhaustively with DCM. Theorganic layers were dried over Na₂SO₄ and concentrated in vacuo. Thecrude material was purified by flash chromatography (silica gel, 120 g,0% to 4% MeOH in DCM) to afford 0.471 g (44%) of the title compound as awhite solid. (M+H)⁺=598 m/e. ¹H NMR (300 MHz, CHLOROFORM-d) δ: 8.68 (s,1H), 8.46 (d, J=2.6 Hz, 2H), 8.29 (d, J=2.6 Hz, 1H), 7.79 (dd, J=8.3,2.3 Hz, 1H), 7.64-7.69 (m, 1H), 7.53-7.63 (m, 3H), 7.50 (t, J=2.1 Hz,1H), 7.47 (d, J=1.5 Hz, 1H), 7.00 (d, J=8.7 Hz, 1H), 4.43 (s, 2H), 3.92(s, 3H), 3.11 (s, 6H), 1.43 (s, 9H).

Preparation of I-21 Step 1. Preparation of6-Chloro-4-[5-(4-hydroxy-4-methyl-piperidine-1-carbonyl)-pyridin-2-ylamino]-2-methyl-2H-pyridazin-3-one

In a 250 mL round-bottomed flask,6-(6-chloro-2-methyl-3-oxo-2,3-dihydropyridazin-4-ylamino)nicotinic acid(195 mg, 695 μmol), 4-methylpiperidin-4-ol (80.0 mg, 695 μmol), HOBT(138 mg, 903 μmol) and Hunig's base (269 mg, 364 μl, 2.08 mmol) werecombined with DMF (13 ml) to give a light yellow suspension. EDC (173mg, 903 μmol) was added and the reaction mixture was heated to 100° C.and stirred for 24 h. Additional 4-methylpiperidin-4-ol (80.0 mg, 695μmol), HOBT (106 mg, 695 μmol) and EDC (133 mg, 695 μmol) were addedwith 2 ml DMF. The reaction mixture was heated to 100° C. and stirredfor 24 h. The reaction was cooled to 25° C. and quenched with water. Theaqueous layer was back-extracted with EtOAc (3×75 mL). The organiclayers were combined, washed with sat NaCl (1×50 mL), dried over Na₂SO₄and concentrated in vacuo. The residue was taken up in DCM/MeOH 9:1 andfiltered. The filtrate was conc. in vacuo to give a light yellow solid.The crude material was purified by flash chromatography (silica gel, 12g, 0% to 10% MeOH in DCM) to afford 0.033 g (13%) of the title compoundas a yellow solid. (M+H)⁺=378/380 m/e.

Step 2. Preparation of Acetic acid2-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-6-{5-[5-(4-hydroxy-4-methyl-piperidine-1-carbonyl)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-benzylester

To a 10 mL microwave vial was added6-chloro-4-(5-(4-hydroxy-4-methylpiperidine-1-carbonyl)pyridin-2-ylamino)-2-methylpyridazin-3(2H)-one(33 mg, 87.3 μmol),2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate (56.1 mg, 114 μmol) and Cs₂CO₃ (99.6 mg, 306 μmol) in dioxane (5ml) and water (0.5 ml). The yellow suspension was purged with argon andPdCl₂(DPPF) (7.13 mg, 8.73 μmol) was added. The vial was capped andheated in the microwave at 125° C. for 30 min. The reaction was cooledto 25° C. and diluted with DCM. Na₂SO₄ was added and the mixture wasfiltered through celite. The filter cake was washed with DCM until clearand the yellow filtrate was conc. in vacuo to afford the title compoundas a brown solid in quantitative yield. (M−H)⁺=708 m/e.

Example 21 Step 3. Preparation of6-tert-butyl-8-fluoro-2-(2-hydroxymethyl-3-{5-[5-(4-hydroxy-4-methyl-piperidine-1-carbonyl)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one

In a 250 mL round-bottomed flask,2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(5-(5-(4-hydroxy-4-methylpiperidine-1-carbonyl)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)benzylacetate (62 mg, 87.4 μmol) was combined with dioxane (5 ml) and 1M LiOH(1 ml) to give a brown solution. The reaction mixture was stirred at 25°C. for 5 h. The crude reaction mixture was concentrated in vacuo andpartitioned between DCM and water. The aqueous layer was back-extractedwith DCM (2×25 mL). The organic layers were combined, washed with satNaCl (1×10 mL), dried over Na₂SO₄ and concentrated in vacuo. The crudematerial was purified by flash chromatography (silica gel, 24 g, 0% to8% MeOH in DCM), isolated as an off-white powder and dried under vacuumfor 3 hrs at 25° C. The material was repurified by flash chromatography(silica gel, 24 g, 0% to 4% MeOH in DCM) to afford 0.008 g (14%) of thetitle compound as a white solid. (M+H)⁺=668 m/e. ¹H NMR (300 MHz,CHLOROFORM-d) δ: 8.69 (s, 1H), 8.39-8.47 (m, 2H), 8.29 (d, J=2.3 Hz,1H), 7.75 (dd, J=8.5, 2.1 Hz, 1H), 7.43-7.70 (m, 5H), 6.99 (d, J=8.7 Hz,1H), 4.43 (br. s., 2H), 3.91 (s, 3H), 3.20-3.87 (m, 4H), 1.65 (br. s.,6H) 1.43 (s, 9H).

Preparation of I-22 Step 1. Preparation of6-(6-Nitro-pyridin-3-yl)-2,6-diaza-spiro[3.3]heptane-2-carboxylic acidtert-butyl ester

In a 25 mL pear-shaped flask, tert-butyl2,6-diazaspiro[3.3]heptane-2-carboxylate (2.81 g, 14.2 mmol),5-bromo-2-nitropyridine (2.88 g, 14.2 mmol), and TEA (1.58 g, 2.17 ml,15.6 mmol) were combined with DMSO (12 ml) to give a light yellowsolution. The reaction mixture was heated to 90° C. and stirred for 40h. Cooled to 25° C. and the reaction mixture was diluted with 50 mL H₂Oand extracted with EtOAc (3×50 mL). The organic layers were combined,washed with sat NaCl (1×50 mL), dried over Na₂SO₄ and concentrated invacuo. The purple oil was used crude in the subsequent reduction.(M+H)⁺=321 m/e.

Step 2. Preparation of6-(6-Amino-pyridin-3-yl)-2,6-diaza-spiro[3.3]heptane-2-carboxylic acidtest-butyl ester

In a 500 mL pear-shaped flask, tert-butyl6-(6-nitropyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (4.54g, 14.2 mmol) and 10% Pd/C (662 mg, 6.22 mmol) were combined with ethylacetate (150 ml) and methanol (50 ml) to give a black suspension. Themixture was evacuated and filled with H₂ twice, then stirred overnightat 25° C. under balloon pressure of H₂. The mixture was filtered overcelite and the filter cake was washed with MeOH. The filtrate wasconcentrated in vacuo to give a purple oily solid. The crude materialwas purified by flash chromatography (silica gel, 12 g, 0% to 4% MeOH inDCM) to afford 1.29 g (31%) of the title compound as an impure dark redsolid. (M+H)⁺=291 m/e.

Step 3. Preparation of6-[6-(6-Chloro-2-methyl-3-oxo-2,3-dihydro-pyridazin-4-ylamino)-pyridin-3-yl]-2,6-diaza-spiro[3.3]heptane-2-carboxylicacid tert-butyl ester

In a 250 mL round-bottomed flask, tert-butyl6-(6-aminopyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (870mg, 3.00 mmol), 4-bromo-6-chloro-2-methylpyridazin-3(2H)-one (670 mg,3.00 mmol), xantphos (260 mg, 449 μmol), Cs₂CO₃ (2.93 g, 8.99 mmol) andPd₂(dba)₃ (137 mg, 150 μmol) were combined with dioxane (25.0 ml) togive a dark brown solution. The reaction mixture was heated to 100° C.under argon and stirred for 20 h. The reaction was cooled to 25° C.,diluted with DCM, and Na₂SO₄ was added. The mixture was filtered overcelite, the filter cake was washed with DCM and the filtrate was conc.in vacuo to a dark brown semisolid. The crude material was purified byflash chromatography (silica gel, 220 g, 0% to 5% MeOH in DCM). Theimpure material was repurified by flash chromatography (silica gel, 220g, 0% to 4% MeOH in DCM) to afford 0.320 g (25%) of the title compoundas a light yellow powder. (M+H)⁺=433/435 m/e. ¹H NMR (300 MHz,CHLOROFORM-d) δ: 8.12 (s, 1H), 8.08 (s, 1H), 7.65 (s, 1H), 6.82 (d,J=1.5 Hz, 2H), 4.12 (s, 4H), 4.01 (s, 3H), 3.80 (s, 4H), 1.45 (s, 9H).

Step 4. Preparation of6-(6-{6-[2-Acetoxymethyl-3-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-phenyl]-2-methyl-3-oxo-2,3-dihydropyridazin-4-ylamino}-pyridin-3-yl)-2,6-diaza-spiro[3.3]heptane-2-carboxylicacid tert butyl ester

In a 250 mL round-bottomed flask, tert-butyl6-(6-(6-chloro-2-methyl-3-oxo-2,3-dihydropyridazin-4-ylamino)pyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate(300 mg, 693 μmol),2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate (445 mg, 901 μmol) and Cs₂CO₃ (677 mg, 2.08 mmol) were combinedwith dioxane (20 ml) and water (2.00 ml) to give a yellow suspension.The flask was evacuated and filled with argon and PdCl₂(DPPF) (17.0 mg,20.8 μmol) was added. The reaction mixture was heated to 85° C. andstirred for 3 h under argon. Additional PdCl₂(DPPF) (17 mg, 20.8 μmol)was added and the reaction mixture was heated to 85° C. and stirred for60 h. Cooled to 25° C. and diluted with DCM. The reaction mixture wasfiltered through celite and the filtrate was dried over Na₂SO₄. Thecrude reaction mixture was concentrated in vacuo. The brown solid wasused crude in the subsequent reaction. (M+H)⁺=765 m/e.

Step 5. Preparation of6-(6-{6-[3-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-2-methyl-3-oxo-2,3-dihydropyridazin-4-ylamino}-pyridin-3-yl)-2,6-diaza-spiro[3.3]heptane-2-carboxylicacid tert butyl ester

In a 250 mL round-bottomed flask, tert-butyl6-(6-(6-(2-(acetoxymethyl)-3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)phenyl)-2-methyl-3-oxo-2,3-dihydropyridazin-4-ylamino)pyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate(530 mg, 693 μmol) was combined with dioxane (15 ml) and 1M LiOH (3 ml)to give a dark brown solution. The reaction mixture was stirred at 25°C. for 4 h. The crude reaction mixture was concentrated in vacuo. Thecrude material was purified by flash chromatography (silica gel, 220 g,0% to 4% MeOH in DCM) to afford 0.169 g (34%) of the title compound as alight yellow powder. (M+H)'=723 m/e. ¹H NMR (300 MHz, CHLOROFORM-d) δ:8.36 (s, 1H), 8.26 (d, J=2.6 Hz, 1H), 8.19 (s, 1H), 7.37-7.69 (m, 6H),6.84-6.94 (m, 1H), 6.80 (d, J=3.0 Hz, 1H), 4.39 (d, J=6.8 Hz, 2H), 4.08(s, 4H), 3.96 (s, 4H), 3.85 (s, 3H), 1.42 (s, 9H), 1.39 (s, 9H).

Step 6. Preparation of6-tert-butyl-2-(3-{5-[5-(2,6-diaza-spiro[3.3]hept-2-yl)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-2-hydroxymethyl-phenyl)-8-fluoro-2H-phthalazin-1-one

In a 250 mL round-bottomed flask, tert-butyl6-(6-(6-(3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-2-(hydroxymethyl)phenyl)-2-methyl-3-oxo-2,3-dihydropyridazin-4-ylamino)pyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate(169 mg, 234 μmol) was combined with DCM (10 ml) and TFA (2 ml) to givea yellow solution. The reaction mixture was stirred at 25° C. for 21 h.Conc. in vacuo to afford the title compound as a yellow solid inquantitative yield. (M+H)⁺=623 m/e.

Example 22 Step 7. Preparation of6-tert-butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(6-methyl-2,6-diaza-spiro[3.3]hept-2-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one

In a 25 mL round-bottomed flask,2-(3-(5-(5-(2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-(hydroxymethyl)phenyl)-6-tert-butyl-8-fluorophthalazin-1(2H)-one(146 mg, 234 μmol), 30% formaldehyde (42.2 mg, 38.8 μl, 1.41 mmol) andsodium cyanoborohydride (177 mg, 2.81 mmol) were combined with methanol(9 ml) to give an orange solution. The reaction mixture was stirred at25° C. for 4 h. The crude reaction mixture was concentrated in vacuo,diluted with 10 mL 0.1 M NaOH and extracted with DCM (3×15 mL). Theorganic layers were dried over Na₂SO₄ and concentrated in vacuo. Thecrude material was purified by flash chromatography (silica gel, 40 g,0% to 10% MeOH in DCM). The light yellow powder was dried under vacuumat 25° C. for 3 hrs to give 0.33 g (22%) of the title compound.(M+H)⁺=637 m/e. ¹H NMR (300 MHz, CHLOROFORM-d) δ: 8.37 (s, 1H), 8.28 (d,J=2.3 Hz, 1H), 8.13 (s, 1H), 7.38-7.71 (m, 6H), 6.75-6.93 (m, 2H), 4.40(s, 2H), 3.96 (s, 4H), 3.88 (s, 3H), 3.47 (s, 4H), 2.37 (s, 3H), 1.42(s, 9H).

Preparation of I-23 Step 1. Preparation of5-Bromo-2-(2,2,5,5-tetramethyl-[1,2,5]azadisilolidin-1-yl)-pyridine

In a 500 mL three-necked flask, 5-bromopyridin-2-amine (5 g, 28.9 mmol)was combined with THF (80 ml) to give a light yellow solution. Cooled to−78° C. and n-butyllithium in hexane (18.2 ml, 29.2 mmol) was added viasyringe. The reaction was stirred at −78° C. for 1 hr, then1,2-bis(chlorodimethylsilyl)ethane (6.22 g, 28.9 mmol) was addeddropwise over 15 min. After stirring for 90 min at −78° C.,n-butyllithium in hexane (18.2 ml, 29.2 mmol) was added. The reactionwas allowed to warm to 25° C. and stirred for 2 hr. The reaction mixturewas diluted with 50 mL sat NaCl and extracted with diethyl ether (2×200mL). The organic layers were combined, washed with H₂O (1×25 mL), satNaCl (1×25 mL), dried over MgSO₄ and concentrated in vacuo. The crudebrown oil was purified by vacuum distillation (1 mm Hg, 170° C.). Theproduct solidified upon cooling to give 4.89 g (54%) of the titlecompound as a white crystalline solid. ¹H NMR (300 MHz, CHLOROFORM-d) δ:8.15 (d, J=2.6 Hz, 1H), 7.47 (dd, J=8.9, 2.5 Hz, 1H), 6.47 (d, J=8.7 Hz,1H), 0.83 (s, 4H), 0.24-0.38 (m, 12H).

Step 2. Preparation of 5-(ethylthio)pyridin-2-amine

In a 100 mL round-bottomed flask,5-bromo-2-(2,2,5,5-tetramethyl-1,2,5-azadisilolidin-1-yl)pyridine (519mg, 1.65 mmol), ethanethiol (102 mg, 122 μl, 1.65 mmol), xantphos (47.6mg, 82.3 μmol) and Hunig's base (425 mg, 575 μl, 3.29 mmol) werecombined with dioxane (10.0 ml) to give a light yellow solution.Pd₂(dba)₃ (37.7 mg, 41.1 μmol) was added and the mixture was evacuatedand filled with Argon. The reaction mixture was heated to 110° C. andstirred for 17 h under argon. The mixture was cooled to 25° C. and conc.in vacuo. The residue was partitioned between 1M HCl and ether.Separated and basified aqueous phase with 3M NaOH. The aqueous layer wasextracted with EtOAc (2×125 mL). The organic layers were combined,washed with H₂O (1×50 mL), sat NaCl (1×25 mL), dried over Na₂SO₄ andconcentrated in vacuo to an orange oil. The oil was dried overnight at25° C. under vacuum to give an orange gum that was used crude in thesubsequent oxidation. (M+H)⁺=155 m/e.

Step 3. Preparation of 5-(Ethanesulfonyl)-pyridin-2-amine

In a 250 mL round-bottomed flask, 5-(ethylthio)pyridin-2-amine (254 mg,1.65 mmol), TFA (376 mg, 254 μL, 3.29 mmol) and m-CPBA (625 mg, 3.62mmol) were combined with DCM (6 mL) to give a light yellow solution. Thereaction mixture was stirred at 0° C. for 2 h. The heavy suspension wasquenched with Aq Na₂SO₃ and diluted with DCM. The phases were separatedand the aqueous layer was back-extracted with DCM (2×20 mL). The organiclayers were combined, washed with sat NaHCO₃ (1×15 mL), sat NaCl (1×15mL), dried over Na₂SO₄ and concentrated in vacuo. The crude material waspurified by flash chromatography (silica gel, 24 g, 0% to 90% EtOAc inheptane) to afford 0.183 g (60%) of the title compound as a whitepowder. (M+H)⁺=187 m/e. ¹H NMR (300 MHz, CHLOROFORM-d) δ: 8.53 (d, J=2.6Hz, 1H), 7.82 (dd, J=8.7, 2.3 Hz, 1H), 6.55 (d, J=8.7 Hz, 1H), 5.23 (br.s., 2H), 3.09 (q, J=7.6 Hz, 2H), 1.29 (t, 3H).

Step 4. Preparation of6-Chloro-4-(5-ethanesulfonyl-pyridin-2-ylamino)-2-methyl-2H-pyridazin-3-one

In a 250 mL round-bottomed flask, 5-(ethylsulfonyl)pyridin-2-amine (183mg, 983 mmol), 4-bromo-6-chloro-2-methylpyridazin-3(2H)-one (263 mg,1.18 mmol), xantphos (85.3 mg, 147 μmol) and Cs₂CO₃ (960 mg, 2.95 mmol)were combined with dioxane (10 mL) to give a light brown suspension. Theflask was evacuated and filled with argon. Pd₂(dba)₃ (45.0 mg, 49.1mmol) was added and the reaction mixture was stirred at 100° C. for 20 hunder argon. Cooled to 25° C. and diluted with DCM. The reaction mixturewas filtered through celite and the filter cake was washed with DCMuntil clear. The filtrate was concentrated and purified by flashchromatography (silica gel, 40 g, 0% to 2% MeOH in DCM) to afford 0.323g (25%) of the title compound as a tan powder. (M+H)⁺=329/331 m/e. ¹HNMR (300 MHz, DMSO-d₆) δ: 10.18 (s, 1H), 8.78 (d, J=2.3 Hz, 1H), 8.12(dd, J=8.9, 2.5 Hz, 1H), 7.74 (d, J=9.1 Hz, 1H), 3.69 (s, 3H), 3.32 (q,J=7.4 Hz, 2H), 1.11 (t, J=7.4 Hz, 3H).

Step 5. Preparation of Acetic acid2-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-6-[5-(5-ethanesulfonyl-pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl]-benzylester

In a 250 mL round-bottomed flask,6-chloro-4-(5-(ethylsulfonyl)pyridin-2-ylamino)-2-methylpyridazin-3(2H)-one(79 mg, 240 μmol),2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate (154 mg, 312 μmol) and Cs₂CO₃ (235 mg, 721 μmol) were combinedwith dioxane (10 ml) and water (1 ml) to give a light yellow suspension.The mixture was evacuated and filled with argon. PdCl₂(DPPF) (9.81 mg,12.0 μmol) was added, the reaction mixture was purged with argon andheated to 85° C. for 60 h. The reaction mixture was diluted with DCM andfiltered through celite. The filter cake was washed with DCM untilclear. The filtrate was dried over Na₂SO₄ and concentrated in vacuo togive a dark brown oil. The brown oil was used crude in the subsequentreaction. (M−H)⁺=659 m/e.

Example 23 Step 6. Preparation of6-tert-Butyl-2-{3-[5-(5-ethanesulfonyl-pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl]-2-hydroxymethyl-phenyl}-8-fluoro-2H-phthalazin-1-one

In a 250 mL round-bottomed flask,2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(5-(5-(ethylsulfonyl)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)benzylacetate (159 mg, 241 μmol) was combined with dioxane (5 ml) and 1M LiOH(1 ml) to give a brown solution. The reaction mixture was stirred at 25°C. for 18 h. The crude reaction mixture was concentrated in vacuo. Theresidue was partitioned between water and DCM. The organic layer wasdried over MgSO₄ and concentrated in vacuo. The crude material waspurified by flash chromatography (silica gel, 24 g, 0% to 4% MeOH inDCM) to afford 0.039 g (54%) of the title compound as a tan solid.(M−H)⁺=617 m/e. ¹H NMR (300 MHz, CHLOROFORM-d) δ: 8.85 (d, J=2.3 Hz,1H), 8.79 (s, 1H), 8.63 (s, 1H), 8.30 (d, J=2.3 Hz, 1H), 8.06 (dd,J=8.7, 2.3 Hz, 1H), 7.43-7.73 (m, 5H), 7.07 (d, J=8.7 Hz, 1H), 4.45 (s,2H), 3.94 (s, 3H), 3.15 (d, J=7.2 Hz, 2H), 1.44 (s, 9H), 1.33 (t, J=7.2Hz, 3H).

Example 24 Preparation of6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-6-oxo-5-[5-(propane-2-sulfonyl)-pyridin-2-ylamino]-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one

Preparation by a similar procedure to Example 23, except substitutingpropane-2-thiol for ethanethiol in step 2 afforded 0.033 g (12%) of thetitle compound as a tan solid. (M+H)⁺=633 m/e. ¹H NMR (300 MHz,CHLOROFORM-d) δ: 8.81 (d, J=2.3 Hz, 1H), 8.73-8.79 (m, 1H), 8.62 (s,1H), 8.29 (d, J=2.3 Hz, 1H), 8.04 (dd, J=8.7, 2.3 Hz, 1H), 7.43-7.70 (m,5H), 7.07 (d, J=8.7 Hz, 1H), 4.45-4.59 (d, 2H), 3.94 (s, 3H), 3.21 (m,J=6.8 Hz, 1H), 1.44 (s, 9H), 1.34 (d, J=6.8 Hz, 6H).

Preparation of I-25 Step 1. Preparation of2-(6-Aminopyridin-3-ylthio)-ethanol

In a 100 mL round-bottomed flask,5-bromo-2-(2,2,5,5-tetramethyl-1,2,5-azadisilolidin-1-yl)pyridine (502mg, 1.59 mmol), 2-mercaptoethanol (124 mg, 112 μl, 1.59 mmol), xantphos(46.1 mg, 79.6 μmol) and Hunig's base (411 mg, 556 μl, 3.18 mmol) werecombined with dioxane (10.0 ml) to give a light yellow solution.Pd₂(dba)₃ (36.4 mg, 39.8 μmol) was added and the mixture was evacuatedand filled with argon. The reaction mixture was heated to 110° C. andstirred for 17 h under argon. The reaction mixture was cooled to 25° C.,concentrated in vacuo and partitioned between 1M HCl and EtOAc.Separated and basified aqueous with 3M NaOH. The aqueous layer wasextracted with EtOAc (3×125 mL). The organic layers were combined,washed with sat NaCl (1×25 mL), dried over Na₂SO₄ and concentrated invacuo to a light yellow solid. The solid was dried under vacuum at 25°C. for 21 hrs to afford 0.259 g (96%) of the title compound. ¹H NMR (300MHz, DMSO-d₆) δ: 7.94 (d, J=2.3 Hz, 1H), 7.45 (dd, J=8.7, 2.3 Hz, 1H),6.40 (d, J=8.7 Hz, 1H), 6.03-6.20 (m, 2H), 4.77 (t, J=5.7 Hz, 1H),3.37-3.51 (m, 2H), 2.67-2.76 (m, 2H).

Example 25 Step 2. Preparation of6-tert-Butyl-8-fluoro-2-(3-{5-[5-(2-hydroxyethylthio)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-2-hydroxymethyl-phenyl)-2H-phthalazin-1-one

In a 250 mL round-bottomed flask, 2-(6-aminopyridin-3-ylthio)ethanol(247 mg, 1.45 mmol),2-(5-bromo-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-6-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)benzylacetate (806 mg, 1.45 mmol), xantphos (126 mg, 218 μmol) and Cs₂CO₃(1.42 g, 4.35 mmol) were combined with dioxane (20 ml) to give a brownsuspension. The reaction was evacuated and filled with argon. Pd₂(dba)₃(66.4 mg, 72.5 μmol) was added and the reaction mixture was heated to100° C. and stirred for 17 h under argon. Cooled to 25° C. and dilutedwith DCM. The reaction mixture was filtered over celite and the filtercake was washed with DCM until clear. The filtrate was conc. in vacuo.The crude material was purified by flash chromatography (silica gel, 40g, 0% to 3% MeOH in DCM). The material was repurified by flashchromatography (silica gel, 40 g, 0% to 50% Acetone in Heptane),concentrated in vacuo to a white powder and dried under vacuum at 25° C.overnight. The product was taken up in dioxane (15 ml) and 1M LiOH (3ml) was added. The reaction was stirred at 25° C. for 17 hrs. The crudereaction mixture was concentrated in vacuo. The residue was diluted with15 mL DCM and 15 mL H₂O. The aqueous layer was back-extracted with DCM(2×20 mL). The organic layers were dried over Na₂SO₄ and concentrated invacuo. The crude material was purified by flash chromatography (silicagel, 40 g, 0% to 50% acetone in heptane) to afford 0.061 g (7%) of thetitle compound as a white powder. (M+H)⁺=603 m/e.

¹H NMR (300 MHz, CHLOROFORM-d) δ: 8.61 (s, 1H), 8.42 (d, J=2.3 Hz, 1H),8.38 (s, 1H), 8.29 (d, J=2.6 Hz, 1H), 7.73 (dd, J=8.5, 2.5 Hz, 1H), 7.65(d, J=1.5 Hz, 1H), 7.60 (d, J=7.6 Hz, 1H), 7.53-7.57 (m, 2H), 7.45-7.51(m, 1H), 6.95 (d, J=8.3 Hz, 1H), 4.43 (s, 2H), 3.92 (s, 3H), 3.74 (t,J=5.9 Hz, 2H), 3.04 (t, J=5.9 Hz, 2H), 1.43 (s, 9H).

Example 26 Preparation of6-tert-Butyl-8-fluoro-2-(3-{5-[5-(2-hydroxyethanesulfonyl)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-2-hydroxymethyl-phenyl)-2H-phthalazin-1-one

In a 100 mL round-bottomed flask,6-tert-butyl-8-fluoro-2-(3-(5-(5-(2-hydroxyethylthio)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-(hydroxymethyl)phenyl)phthalazin-1(2H)-one(45 mg, 74.7 μmol) was combined with DCM (4 ml) to give a light yellowsolution. The mixture was cooled to 0° C. and TFA (17.0 mg, 11.5 μA, 149μmol) and m-CPBA (28.3 mg, 164 μmol) were added. The reaction wasstirred at 0° C. for 3 hrs. The reaction was quenched with sat'd Na₂SO₃and 1M NaOH. Diluted with DCM (emulsion) and separated. The aqueouslayer was back-extracted with DCM (3×20 mL). The organic layers werecombined, washed with sat NaCl (1×15 mL), dried over MgSO₄ andconcentrated in vacuo. The crude material was purified by flashchromatography (silica gel, 12 g, 0% to 50% acetone in heptane) toafford 0.010 g (22%) of the title compound as a white powder.

(M+H)⁺=634 m/e. ¹H NMR (300 MHz, CHLOROFORM-d) δ: 8.87 (d, J=2.3 Hz,1H), 8.80 (s, 1H), 8.66 (s, 1H), 8.30 (d, J=2.3 Hz, 1H), 8.07 (dd,J=8.7, 2.6 Hz, 1H), 7.45-7.68 (m, 5H), 7.08 (d, J=8.7 Hz, 1H), 4.45 (s,2H), 4.01-4.09 (m, 2H), 3.93 (s, 3H), 3.34-3.42 (m, 2H), 1.44 (s, 9H).

Preparation of I-27 Example 276-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{5-[5-(4-isopropyl-piperazin-1-yl)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-oneHCl

Step 1

To 5-bromo-2-nitropyridine (1.0 g, 4.93 mmol, Eq: 1.00) in DMSO (10.0ml) was added 1-isopropylpiperazine (632 mg, 4.93 mmol, Eq: 1.00), andthe resulting solution was heated at 70° C. for 18 hours. The solutionwas cooled to room temperature. The solution was diluted with 50 mlwater. The resulting solid was filtered. The solid was washed with waterand dried under vacuum. The crude material was purified by flashchromatography (silica gel, 80 g, 0% to 3% MeOH/DCM gradient) to give1-isopropyl-4-(6-nitropyridin-3-yl)piperazine (788 mg, 64%). LC/MS-ESIobserved [M+H]⁺ 251.

Step 2

In a 250 mL round-bottomed flask,1-isopropyl-4-(6-nitropyridin-3-yl)piperazine (788 mg, 3.15 mmol, Eq:1.00) in EtOH (40 ml) was combined with palladium on carbon(DeGussa)(78.2 mg, 735 μmol, Eq: 0.233). The mixture was evacuated twicewith hydrogen and then stirred under a hydrogen atmosphere for 18 h. Thesolution was filtered through celite, rinsing the celite with freshethanol. The solvent was evaporated under reduced pressure to give5-(4-isopropylpiperazin-1-yl)pyridin-2-amine (425 mg, 61%). LC/MS-ESIobserved [M+H]⁺ 221.

Step 3

In a 50 mL round-bottomed flask,5-(4-isopropylpiperazin-1-yl)pyridin-2-amine (200 mg, 908 μl mmol, Eq:1.00), 4-bromo-6-chloro-2-methylpyridazin-3(2H)-one (243 mg, 1.09 mmol,Eq: 1.2) and cesium carbonate (887 mg, 2.72 mmol, Eq: 3) were combinedwith dioxane (20 ml) to give a orange suspension.4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (78.8 mg, 136 mmol, eq:0.15) was added. Tris(dibenzylideneacetone)dipalladium(0) (41.6 mg, 45.4μmol, Eq: 0.05) was added. The solution was degassed with Ar for 10 min.The solution was heated at 95-105° C. for 48 h. The solution was dilutedwith 200 ml DCM. MgSO₄ was added and the suspension stirred for 10 min.The solid was filtered and washed several times with DCM. The organicswere concentrated in vacuo. The crude material was purified by flashchromatography (silica gel, 40 g, 50% to 100% EtOAc/hexanes gradient) togive6-chloro-4-(5-(4-isopropylpiperazin-1-yl)pyridin-2-ylamino)-2-methylpyridazin-3(2H)-one(273 mg, 83%). LC/MS-ESI observed [M+H]⁺ 363.

Step 4

6-Chloro-4-(5-(4-isopropylpiperazin-1-yl)pyridin-2-ylamino)-2-methylpyridazin-3(2H)-one(123 mg, 340 μmol, Eq: 1.2),2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate (140 mg, 283 μmol, Eq: 1.00), potassium phosphate tribasic (180mg, 850 μmol, Eq: 3.00) and X-PHOS (13.5 mg, 28.3 μmol, Eq: 0.10) weredissolved in dioxane (10 ml) and water (1.0 mL). The reaction wasdegassed with Ar. Pd2(dba)₃ (13.0 mg, 14.2 μmol, Eq: 0.05) was added andthe reaction was heated to 125° C. for 30 min in the microwave. Thesolution was dried over MgSO₄ and filtered. Concentrated in vacuo. Thecrude material was purified by flash chromatography (silica gel, 12 g,0% to 5% MeOH/DCM gradient) to give2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(5-(5-(4-isopropylpiperazin-1-yl)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)benzylacetate (153 mg, 78%). LC/MS-ESI observed [M+H]⁺ 695.

Step 5

To2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(5-(5-(4-isopropylpiperazin-1-yl)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)benzylacetate (153 mg, 220 mmol, Eq: 1.00) in THF (2.0 ml) was added anaqueous solution of 1N NaOH (2.0 mL, 2.00 mmol, Eq: 9.08). The resultingsolution heated at 60° C. for 2 h. The mixture was cooled to roomtemperature. The solution was diluted with saturated NaHCO₃ and DCM. Thelayers were separated. The aqueous layer was extracted three times withDCM. The combined organics were dried over MgSO₄. The solution wasfiltered. Concentrated in vacuo. The crude material was purified byflash chromatography (silica gel, 12 g, 0% to 50%(60:10:1DCM:MeOH:NH₄OH)/DCM gradient) to give a cream solid. The solidwas triturated with Et₂O. The solid was filtered, then dissolved in 2 mlDCM. A solution of 1.0 M HCl in Et₂O (2 ml) was added. A solid formed.The solid was filtered and dried under vacuum to give6-tert-butyl-8-fluoro-2-(2-hydroxymethyl-3-{5-[5-(4-isopropyl-piperazin-1-yl)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-oneHCl (57.5 mg, 38%). LC/MS-ESI observed [M+H]⁺ 653. ¹H NMR (300 MHz,DMSO-d₆) δ ppm 1.28 (d, J=6.80 Hz, 6H) 1.37 (s, 9H) 3.08 (d, J=11.33 Hz,2H) 3.46 (d, J=10.20 Hz, 2H) 3.76 (s, 5H) 4.39 (d, J=6.04 Hz, 2 H)7.41-7.59 (m, 5H) 7.73 (d, J=13.97 Hz, 1H) 7.86 (s, 1H) 8.06 (d, J=2.27Hz, 1H) 8.42 (s, 1H) 8.50 (d, J=2.27 Hz, 1H) 9.31 (s, 1H)

Preparation of I-28 Example 286-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(1-methyl-pyrrolidin-3-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one

Step 1

In a 100 mL three-necked flask, a solution of tert-butyl3-oxopyrrolidine-1-carboxylate (1 g, 5.24 mmol, Eq: 1.00) in THF (30.0ml) was treated with lithium bis(trimethylsilyl)amide 1M in THF (5.6 ml,5.6 mmol, Eq: 1.07) at −78° C. After stirring for 15 min at −78° C., asolution of N-phenylbis(trifluoromethanesulfonimide) (2.27 g, 6.28 mmol,Eq: 1.20) in THF (10 ml) was added by drop. The reaction mixture wasthen warmed to room temperature. The reaction was quenched with theaddition of saturated aqueous NaHCO₃, and then extracted with ethylether. The organic layer was washed with brine, dried over MgSO₄,filtered and concentrated in vacuo. The crude material was purified byflash chromatography (silica gel, 120 g, 0% to 30% EtOAc/Hex gradient)to give 3-trifluoromethanesulfonyloxy-2,5-dihydro-pyrrole-1-carboxylicacid tert-butyl ester (880 mg, 53%).

Step 2

In a 25 mL round-bottomed flask,3-trifluoromethanesulfonyloxy-2,5-dihydro-pyrrole-1-carboxylic acidtert-butyl ester (780 mg, 2.46 mmol, Eq: 1.00) was combined with THF (20ml) to give a colorless solution. The solution was purged with argon for10 min. Potassium carbonate (1.72 g, 12.3 mmol, Eq: 5.0),5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (649 mg,2.95 mmol, Eq: 1.20), tetrakis(triphenylphosphine)palladium(0) (28.4 mg,24.6 μmol, Eq: 0.01) and water (200 μl) were added. The reaction mixturewas heated to 70° C. and stirred for 16 h. The reaction mixture waspoured into saturated NaHCO₃ and extracted twice with Et₂O. The organiclayer was washed with brine, dried over Na₂SO₄ and concentrated invacuo. The crude material was purified by flash chromatography (silicagel, 40 g, 50% (60:10:1 DCM:MeOH:NH₄OH)/DCM) to give3-(6-amino-pyridin-3-yl)-2,5-dihydro-pyrrole-1-carboxylic acidtert-butyl ester (538 mg, 84%). LC/MS-ESI observed [M+H]⁺ 262.

Step 3

3-(6-Amino-pyridin-3-yl)-2,5-dihydro-pyrrole-1-carboxylic acidtert-butyl ester (538 mg, 2.06 mmol, Eq: 1.00) was dissolved in methanol(20 ml). The solution was put under argon and then treated withpalladium on activated carbon (43.8 mg, 20.6 μmol, Eq: 0.01). Thesuspension was purged with hydrogen and stirred under hydrogen for 18 h.The reaction mixture was filtered through silica gel. The filtrate wasconcentrated and the residue was dissolved in methanol (12 ml). Thesolution was purged with argon for 10 min and then treated withpalladium on activated carbon (Degussa) (43.8 mg, 20.6 μmol, Eq: 0.01).The suspension was purged with hydrogen and stirred under hydrogen for18 h. The reaction mixture was filtered through a 45 μm frit. Thefiltrate was concentrated in vacuo to give tert-butyl3-(6-aminopyridin-3-yl)pyrrolidine-1-carboxylate (422 mg, 78%).LC/MS-ESI observed [M+H]⁺ 264.

Step 4

Tert-butyl 3-(6-aminopyridin-3-yl)pyrrolidine-1-carboxylate (422 mg, 1.6mmol, Eq: 1.00), 4-bromo-6-chloro-2-methylpyridazin-3(2H)-one (430 mg,1.92 mmol, Eq: 1.20), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene(139 mg, 240 μmol, Eq: 0.15), cesium carbonate (1.57 g, 4.81 mmol, Eq:3) and tris(dibenzylideneacetone)dipalladium(0) (73.4 mg, 80.1 μmol, Eq:0.05) were combined in dioxane (10 ml). The solution was degassed withAr for 10 min. The mixture was heated at 100° C. for 18 h. The solutionwas cooled to room temperature then diluted with 100 ml DCM. Theorganics washed with water, then dried over MgSO₄. The solution wasfiltered. Concentrated in vacuo. The crude material was purified byflash chromatography (silica gel, 40 g, 50% to 100% EtOAC/Hex gradient)to give tert-butyl3-(6-(6-chloro-2-methyl-3-oxo-2,3-dihydropyridazin-4-ylamino)pyridin-3-yl)pyrrolidine-1-carboxylate(325 mg, 50%) LC/MS-ESI observed [M+H]⁺ 406.

Step 5

Tert-butyl3-(6-(6-chloro-2-methyl-3-oxo-2,3-dihydropyridazin-4-ylamino)pyridin-3-yl)pyrrolidine-1-carboxylate(160 mg, 394 μmol, Eq: 1.00) was dissolved in a solvent mixture offormic acid (6.0 ml) and formaldehyde, 37% (12.0 ml). The solutionstirred at 70° C. for 18 h. The solution was cooled to room temperature.Water was added. The reaction mixture was extracted once with DCM. SolidK₂CO₃ was slowly added to the aqueous layer until the pH=14. A solidformed that was subsequently filtered. The solid was dried to give6-chloro-2-methyl-4-(5-(1-methylpyrrolidin-3-yl)pyridin-2-ylamino)pyridazin-3(2H)-one(70 mg, 55%). LC/MS-ESI observed [M+H]⁺ 320.

Step 6

In a 50 mL test tube,6-chloro-2-methyl-4-(5-(1-methylpyrrolidin-3-yl)pyridin-2-ylamino)pyridazin-3(2H)-one(69 mg, 216 μmol, Eq: 1.00) and2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate (128 mg, 259 μmol, Eq: 1.20) were combined with BuOH (4 ml) togive an orange solution. Water (1.0 ml) was added, followed by X-PHOS(10.3 mg, 21.6 μmol, Eq: 0.1) and potassium phosphate tribasic (91.6 mg,432 μmol, Eq: 2). Bis(dibenzylideneacetone)palladium (6.2 mg, 10.8 μmol,Eq: 0.05) was added. The solution was purged with argon. The reactionmixture was warmed in a oil bath at 110° C. for 1.5 hours. The solutionwas allowed to cool to room temperature. The reaction mixture was pouredinto 75 mL H₂O and extracted with EtOAc. The organic layer wasconcentrated in vacuo. The crude material was purified by flashchromatography (silica gel, 12 g, 50% to 100% (60:10:1DCM:MeOH:NH₄OH)/DCM gradient) to give a mixture of products2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(1-methyl-5-(5-(1-methylpyrrolidin-3-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridazin-3-yl)benzylacetate and6-tert-butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(1-methyl-pyrrolidin-3-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one(1:7 ratio, 109 mg total, 75% overall). LC/MS-ESI observed [M+H]⁺ 652,610.

Step 7

To a mixture of2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(1-methyl-5-(5-(1-methylpyrrolidin-3-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridazin-3-yl)benzylacetate and6-tert-butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(1-methyl-pyrrolidin-3-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one(106 mg, 163 μmol, Eq: 1.00) in THF (2.0 ml) was added aqueous 1N NaOH(1.95 ml, 1.95 mmol, Eq: 12.0). The solution was heated to 60° C. for 18h. The solution was cooled to room temperature. The solution was dilutedwith saturated NaHCO₃ and DCM. The layers were separated. The aqueouslayer was extracted three times with DCM, and then dried over Na₂SO₄.Concentrated in vacuo. The resulting solid was triturated with Et₂O. Thesolid was filtered. The mother liquor was evaporated to give a whitesolid. The solid was dried at 50° C. under reduced pressure for 18 h togive6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(1-methyl-pyrrolidin-3-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one(41 mg, 41%). LC/MS-ESI observed [M+H]⁺ 610. ¹H NMR (300 MHz,CHLOROFORM-d) δ ppm 1.45 (s, 9H) 1.86 (dd, J=13.03, 6.99 Hz, 1H)2.23-2.60 (m, 5H) 2.76 (br. s., 2H) 3.00 (br. s., 1H) 3.24-3.42 (m, 1H)3.91 (s, 4H) 4.43 (d, J=6.04 Hz, 2H) 6.92 (d, J=8.31 Hz, 1H) 7.40-7.78(m, 6H) 8.26 (dd, J=12.65, 2.83 Hz, 3H) 8.62 (s, 1H).

Preparation of I-29 Example 296-tert-Butyl-8-fluoro-2-{2-hydroxymethyl-3-[5-(1′-isopropyl-1′,2′,3′,4′,5′,6′-hexahydro-[3,4′]bipyridinyl-6-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl]-phenyl}-2H-phthalazin-1-one

Step 1

In a 50 mL round-bottomed flask, 5-bromo-2-nitropyridine (3.28 g, 16.2mmol, Eq: 1) and tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate(5 g, 16.2 mmol, Eq: 1.00) were combined with dioxane (80.0 ml) to givea light yellow solution. Cs₂CO₃ (10.5 g, 32.3 mmol, Eq: 2) and 3 mL H₂Owere added. The solution was degassed with Ar beforebis(triphenylphosphine)palladium(ii) dichloride (1.13 g, 1.62 mmol, Eq:0.1) was added. The reaction mixture was heated to 80° C. and stirredfor 15 h. The reaction mixture was poured into 300 mL H₂O and extractedwith EtOAc (3×100 mL). The combined organic extracts were washed withbrine and dried over MgSO₄. The crude reaction mixture was concentratedin vacuo. The crude material was purified by flash chromatography(silica gel, 220 g, 10% to 100% EtOAc/Hex gradient) to give a dark brownimpure solid. The solid was triturated with Et₂O to afford tert-butyl4-(6-nitropyridin-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate (685 mg,69%) as a tan solid. LC/MS-ESI observed [M+H]⁺ 306.

Step 2

In a 250 mL round-bottomed flask, tert-butyl4-(6-nitropyridin-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate (632 mg,2.07 mmol, Eq: 1.00) in EtOH (25.0 ml) and ethyl acetate (10 ml) wascombined with palladium on carbon (66.1 mg, 62.1 μmol, Eq: 0.03). Themixture was evacuated twice with hydrogen and then stirred with ahydrogen-filled balloon for 22 h. The hydrogen was replaced withnitrogen. The solution was filtered through celite. The celite waswashed several times with EtOAc. Concentrated in vacuo to givetert-butyl 4-(6-aminopyridin-3-yl)piperidine-1-carboxylate (635 mg,quantitative yield). LC/MS-ESI observed [M+H]⁺ 278.

Step 3

4-Bromo-6-chloro-2-methylpyridazin-3(2H)-one (509 mg, 2.28 mmol, Eq:1.00), tert-butyl 4-(6-aminopyridin-3-yl)piperidine-1-carboxylate (632mg, 2.28 mmol, Eq: 1.00),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (198 mg, 342 μmol, Eq:0.15) and cesium carbonate (2.6 g, 7.98 mmol, Eq: 3.5) were suspended indioxane (20 ml) under argon. Finallytris(dibenzylideneacetone)dipalladium(0) (156 mg, 171 μmol, Eq: 0.075)was added. The reaction mixture was heated to 90° C. for 18 h. Thereaction mixture was filtered over celite; washed with dioxane, andconcentrated in vacuo. The crude material was purified by flashchromatography (silica gel, 24 g, 20% to 50% EtOAc/Hex gradient) to givetert-butyl4-(6-(6-chloro-2-methyl-3-oxo-2,3-dihydropyridazin-4-ylamino)pyridin-3-yl)piperidine-1-carboxylate(782 mg, 82%). LC/MS-ESI observed [M+H]⁺ 420.

Step 4

To tert-butyl4-(6-(6-chloro-2-methyl-3-oxo-2,3-dihydropyridazin-4-ylamino)pyridin-3-yl)piperidine-1-carboxylate(782 mg, 1.86 mmol, Eq: 1.00) in DCM (20 ml) was added TFA (2.12 g, 1.43ml, 18.6 mmol, Eq: 10). The reaction mixture stirred under nitrogen for18 h. Concentrated in vacuo to give6-chloro-2-methyl-4-(5-(piperidin-4-yl)pyridin-2-ylamino)pyridazin-3(2H)-one(474 mg, 80%). LC/MS-ESI observed [M+H]⁺ 320.

Step 5

To a solution of6-chloro-2-methyl-4-(5-(piperidin-4-yl)pyridin-2-ylamino)pyridazin-3(2H)-one(200 mg, 625 μmol, Eq: 1.00) and acetone (799 mg, 1.01 ml, 13.8 mmol,Eq: 22) in MeOH (5 ml) was added sodium cyanoborohydride (39.3 mg, 625μmol, Eq: 1.00) and acetic acid (656 mg, 625 μl, 10.9 mmol, Eq: 17.5).The reaction mixture stirred under N₂ for 18 h. Additional acetone (1ml) was added, followed by THF (3 ml). The reaction mixture continuedstirring under N₂ for 2 h. Additional sodium cyanoborohydride (19.7 mg,313 μmol, Eq: 0.50) was added. The mixture stirred for 4 h. Concentratedin vacuo. The crude material was purified by flash chromatography(silica gel, 12 g, 50% to 100% (60:10:1 DCM:MeOH:NH₄OH)/DCM gradient) togive6-chloro-4-(5-(1-isopropylpiperidin-4-yl)pyridin-2-ylamino)-2-methylpyridazin-3(2H)-one(220 mg, 97%). LC/MS-ESI observed [M+H]⁺ 362.

Step 6

In a 50 mL test tube,6-chloro-4-(5-(1-isopropylpiperidin-4-yl)pyridin-2-ylamino)-2-methylpyridazin-3(2H)-one(220 mg, 608 μmol, Eq: 1.00) and 1703-100 (288 mg, 608 μmol, Eq: 1.00)were combined with BuOH (12.9 ml). Water (3.24 ml) was added. X-PHOS(29.0 mg, 60.8 μmol, Eq: 0.1) and potassium phosphate tribasic (258 mg,1.22 mmol, Eq: 2) were added. Bis(dibenzylideneacetone)palladium (17.5mg, 30.4 μmol, Eq: 0.05) was added. The solution was purged with argon.The reaction warmed in an oil bath at 100° C. for 18 hours. The solutionwas cooled to room temperature. The reaction mixture was poured into 75mL H₂O and extracted twice with EtOAc. The organic layers were washedwith brine, and then dried over MgSO₄. Concentrated in vacuo. The crudematerial was purified by flash chromatography (silica gel, 12 g, 50% to100% (60:10:1 DCM:MeOH:NH₄OH)/DCM gradient) to give2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(5-(5-(1-isopropylpiperidin-4-yl)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)benzylacetate (248 mg, 59%). LC/MS-ESI observed [M+H]⁺ 694.

Step 7

To a solution of2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(5-(5-(1-isopropylpiperidin-4-yl)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)benzylacetate (248 mg, 357 μmol, Eq: 1.00) in THF (5.0 ml) was added NaOH(4.29 ml, 4.29 mmol, Eq: 12.0). The reaction mixture heated at 60° C.for 18 h. The solution was cooled to room temperature, and then dilutedwith saturated NaHCO₃ and DCM. The layers were separated. The aqueouslayer was extracted three times with DCM. The organic layers werecombined, and then dried over Na₂SO₄. Concentrated in vacuo. The solidwas triturated with Et₂O and dried under vacuum to give6-tert-butyl-8-fluoro-2-{2-hydroxymethyl-3-[5-(1′-isopropyl-1′,2′,3′,4′,5′,6′-hexahydro-[3,4]bipyridinyl-6-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl]-phenyl}-2H-phthalazin-1-one(202 mg, 87%). LC/MS-ESI observed [M+H]⁺ 652. ¹H NMR (300 MHz,CHLOROFORM-d) δ ppm 1.10 (d, J=6.42 Hz, 6H) 1.43 (s, 9H) 1.84 (br. m.,5H) 2.28 (br. m., 2H) 2.50 (br. m., 1H) 2.79 (br. s., 1H) 3.03 (d,J=10.20 Hz, 2H) 3.90 (s, 4H) 4.42 (d, J=6.80 Hz, 2H) 6.92 (s, 1H)7.40-7.73 (m, 6H) 8.17-8.32 (m, 4H) 8.60 (s, 2H)

Preparation of I-30 Preparation of potassium(2-(acetoxymethyl)-3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)phenyl)trifluoroborate

A round-bottomed flask equipped with a bubbler, a thermometer, and amagnetic stirrer was charged with2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-chlorobenzylacetate (10 g, 24.8 mmol, Eq: 1.00),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (9.46 g,37.2 mmol, Eq: 1.5), Pd(OAc)₂ (69.7 mg, 310 μmol, Eq: 0.0125), X-PHOS(296 mg, 621 μmol, Eq: 0.025), and potassium acetate (5.29 g, 53.9 mmol,Eq: 2.17). Reaction mixture was degassed (3 times). Added MeTHF, thenagain degassed (3 times). Mixture was heated at 60° C. over night.Reaction was not finished. Reaction temperature was increased to 65° C.and stirred for 3 hours. HPLC showed that the reaction was completed.The reaction was cooled and 2 N HCl (31.0 ml, 62.1 mmol, Eq: 2.5) wasadded. The mixture was stirred for half an hour, then was passed througha celite plug to remove a black material. The layers were separated. Theorganic layer was washed with water (60.0 g, 60.0 ml) and thenconcentrated to a heavy oil. The oil was dissolved in MeOH (79.2 g, 100ml) and treated with potassium hydrogen fluoride, 3M solution (20.7 ml,62.1 mmol, Eq: 2.5). LC showed reaction was not finished over night.Another 0.5 equivalent of KHF2 was added. The resultant slurry waswarmed at 45° C. for 3 hours. The mixture was stirred over night at roomtemperature. Product was isolated by filtration. Cake was washed withmethanol.

After drying by vacuum, potassium(2-(acetoxymethyl)-3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)phenyl)trifluoroborate(11.26 g, 23.7 mmol, 95.6% yield) was obtained.

Example 30 Preparation of6-tert-Butyl-2-{3-[5-(1′-ethyl-1′,2′,3′,4′,5′,6′-hexahydro-[3,4]bipyridinyl-6-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl]-2-hydroxymethyl-phenyl}-8-fluoro-2H-phthalazin-1-one

Step 1

In a 100 mL round-bottomed flask,6-chloro-2-methyl-4-(5-(piperidin-4-yl)pyridin-2-ylamino)pyridazin-3(2H)-one(179 mg, 560 μmol, Eq: 1.00) and acetaldehyde (247 mg, 316 μl, 5.6 mmol,Eq: 10.0) were combined with THF (5.0 ml) to give a light yellowsolution. Acetic acid (33.6 mg, 32.0 μl, 560 μmol, Eq: 1.00) was added.The reaction mixture was cooled to 0° C. Sodium triacetoxyborohydride(178 mg, 840 μmol, Eq: 1.5) was added. The reaction mixture stirred atroom temperature for 2 h. The reaction was poured into water, and thensaturated NaHCO₃ was added to the solution until it was basic. Thesolution was extracted twice with EtOAc, and then the organic layerswere washed with brine, dried over Na₂SO₄ and concentrated in vacuo togive a solid. The solid was triturated with ether to give6-chloro-4-(5-(1-ethylpiperidin-4-yl)pyridin-2-ylamino)-2-methylpyridazin-3(2H)-one(121 mg, 62%). LC/MS-ESI observed [M+H]⁺ 348.

Step 2

In a 50 mL test tube,6-chloro-4-(5-(1-ethylpiperidin-4-yl)pyridin-2-ylamino)-2-methylpyridazin-3(2H)-one(121 mg, 348 μmol, Eq: 1.00) and potassium(2-(acetoxymethyl)-3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)phenyl)trifluoroborate(165 mg, 348 μmol, Eq: 1.00) were combined with BuOH (4 ml) to give aorange solution. Water (1.00 ml) was added. X-PHOS (16.6 mg, 34.8 μmol,Eq: 0.1) and potassium phosphate tribasic (148 mg, 696 μmol, Eq: 2) wereadded. Bis(dibenzylideneacetone)palladium (10.0 mg, 17.4 μmol, Eq: 0.05)was added. The reaction mixture was purged with argon. The mixture washeated in a oil bath at 100° C. for 1.5 hours, then cooled to roomtemperature. The reaction mixture was poured into 75 mL H₂O andextracted with twice with EtOAc. The organic layers were combined anddried over Na₂SO₄. Concentrated in vacuo. The crude material waspurified by flash chromatography (silica gel, 12 g, 50% to 100% (60:10:1DCM:MeOH:NH₄OH)/DCM gradient) to give a solid. The solid was trituratedwith Et₂O to give2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(5-(5-(1-ethylpiperidin-4-yl)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)benzylacetate (147 mg, 62%). LC/MS-ESI observed [M+H]⁺ 680.

Step 3

To2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(5-(5-(1-ethylpiperidin-4-yl)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)benzylacetate (147 mg, 216 μmol, Eq: 1.00) in MeOH (15 ml) was added potassiumcarbonate (59.8 mg, 432 μmol, Eq: 2.0). The reaction mixture stirred at40° C. for 1 h. The solution was cooled to room temperature.Concentrated in vacuo. The residue was taken up in DCM/water and thelayers were separated. The aqueous layer was extracted once with DCM.The organic layers were combined, and then dried over Na₂SO₄.Concentrated in vacuo. The crude material was purified by flashchromatography (silica gel, 12 g, 25% to 75% (60:10:1DCM:MeOH:NH₄OH)/DCM gradient) to give6-tert-butyl-2-{3-[5-(1′-ethyl-1′,2′,3′,4′,5′,6′-hexahydro-[3,4′]bipyridinyl-6-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl]-2-hydroxymethyl-phenyl}-8-fluoro-2H-phthalazin-1-one(108 mg, 78%). LC/MS-ESI observed [M+H]⁺ 638. ¹H NMR (300 MHz,CHLOROFORM-d) δ ppm 1.16 (br. s., 2H) 1.43 (s, 9H) 1.84 (br. s., 4H)2.06 (br. s., 2H) 2.51 (br. s., 3H) 3.11 (br. s., 2H) 3.69-4.09 (m andoverlapping singlet, 4H) 4.42 (d, J=6.80 Hz, 2H) 6.91 (d, J=8.69 Hz, 1H)7.37-7.77 (m, 6H) 8.11-8.36 (m, 3H) 8.60 (s, 1H)

Preparation of I-31 Example 316-tert-Butyl-2-{3-[5-(1,5-dimethyl-1H-pyrazol-3-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl]-2-hydroxymethyl-phenyl}-8-fluoro-2H-phthalazin-1-one

Step 1

1,5-Dimethyl-1H-pyrazol-3-amine (400 mg, 3.6 mmol, Eq: 1.00) and4-bromo-6-chloro-2-methylpyridazin-3(2H)-one (965 mg, 4.32 mmol, Eq:1.20) were combined with 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene(312 mg, 540 μmol, Eq: 0.15), cesium carbonate (3.52 g, 10.8 mmol, Eq:3) and tris(dibenzylideneacetone)dipalladium(0) (165 mg, 180 μmol, Eq:0.05) in dioxane (10.0 ml). The solution was degassed with Ar. Thereaction mixture heated at 100° C. for 18 h. The mixture was cooled toroom temperature. The solution was diluted with 100 ml DCM. The organiclayer was washed with water. The organic layer was dried over MgSO₄.Concentrated in vacuo. The crude material was purified by flashchromatography (silica gel, 40 g, 10% to 50% (60:10:1DCM:MeOH:NH₄OH)/DCM gradient) to give6-chloro-4-(1,5-dimethyl-1H-pyrazol-3-ylamino)-2-methylpyridazin-3(2H)-one(408 mg, 45%). LC/MS-ESI observed [M+H]⁺ 235.

Step 2

In a 50 mL test tube,6-chloro-4-(1,5-dimethyl-1H-pyrazol-3-ylamino)-2-methylpyridazin-3(2H)-one(100 mg, 394 μmol, Eq: 1.00) and potassium(2-(acetoxymethyl)-3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)phenyl)trifluoroborate(224 mg, 473 μmol, Eq: 1.2) were combined with BuOH (4.00 ml) to give aorange solution. Water (1.00 ml) was added. X-PHOS (18.8 mg, 39.4 μmol,Eq: 0.1) and potassium phosphate tribasic (167 mg, 788 μmol, Eq: 2) wereadded. Bis(dibenzylideneacetone)palladium (11.3 mg, 19.7 μmol, Eq: 0.05)was added. The reaction mixture was purged with argon. The solutionwarmed in a oil bath at 100° C. for 1.5 hours. The solution was allowedto cool to room temperature. The reaction mixture was poured into 75 mLH₂O and extracted with DCM. The organic layer was concentrated in vacuo.The crude material was purified by flash chromatography (silica gel, 25g, 0% to 30% (60:10:1 DCM:MeOH:NH₄OH)/DCM gradient) to give a solid. Thesolid was triturated with Et₂O to give2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(5-(1,5-dimethyl-1H-pyrazol-3-ylamino)-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)benzylacetate (186 mg, 81%). LC/MS-ESI observed [M+H]⁺ 586.

Step 3

To2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(5-(1,5-dimethyl-1H-pyrazol-3-ylamino)-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)benzylacetate (186 mg, 318 μmol, Eq: 1.00) in MeOH (15.0 ml) was addedpotassium carbonate (87.8 mg, 635 μmol, Eq: 2.0). The reaction mixturestirred at 40° C. for 2 h. The solution was cooled to room temperature.Concentrated in vacuo. The residue was taken up in DCM/water. The layerswere separated. The aqueous layer was extracted once with DCM. Theorganic layers were combined, and then dried over Na₂SO₄. Concentratedin vacuo. The crude material was purified by flash chromatography(silica gel, 12 g, 0% to 35% (60:10:1 DCM:MeOH:NH₄OH)/DCM gradient) togive6-tert-butyl-2-{3-[5-(1,5-dimethyl-1H-pyrazol-3-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl]-2-hydroxymethyl-phenyl}-8-fluoro-2H-phthalazin-1-one(75 mg, 44%). LC/MS-ESI observed [M+H]⁺ 544. ¹H NMR (300 MHz,CHLOROFORM-d) δ ppm 1.43 (s, 9H) 2.28 (s, 3H) 3.75 (s, 3H) 3.88 (s, 3H)4.40 (s, 2H) 5.92 (s, 1H) 7.41-7.60 (m, 4H) 7.62-7.69 (m, 1 H) 7.78 (s,1H) 7.96 (s, 1H) 8.29 (d, J=2.64 Hz, 1H)

Preparation of I-32 Example 326-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-[1-methyl-5-[5-((S)-1-methyl-pyrrolidin-3-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl]-phenyl)-2H-phthalazin-1-one

Step 1

In a 500 mL three-necked flask, a solution of tert-butyl3-oxopyrrolidine-1-carboxylate (4.5 g, 23.6 mmol, Eq: 1.00) in with THF(180 ml) was treated with lithium bis(trimethylsilyl)amide 1M in THF(25.2 ml, 25.2 mmol, Eq: 1.07) at −78° C. After stirring 15 min at −78°C., a solution of N-phenylbis(trifluoromethanesulfonimide) (10.2 g, 28.3mmol, Eq: 1.20) in THF (60.0 ml) was added. The reaction mixture wasthen warmed to room temperature. The reaction was quenched with theaddition of saturated aqueous NaHCO₃, and then extracted with ethylether. The organic layer was washed with brine, dried over MgSO₄,filtered and concentrated in vacuo. The crude material was purified byflash chromatography (silica gel, 300 g, 0% to 30% EtOAc in hexanesgradient) to give3-trifluoromethanesulfonyloxy-2,5-dihydro-pyrrole-1-carboxylic acidtert-butyl ester (2.3 g, 31%).

Step 2

In a 250 mL round-bottomed flask,3-trifluoromethanesulfonyloxy-2,5-dihydro-pyrrole-1-carboxylic acidtert-butyl ester (2.3 g, 7.25 mmol, Eq: 1.00) was combined with THF (60ml) to give a colorless solution. The solution was purged with argon for10 min. Potassium carbonate (5.06 g, 36.2 mmol, Eq: 5.0),5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (1.91 g,8.7 mmol, Eq: 1.20), tetrakis(triphenylphosphine)palladium(0) (83.8 mg,72.5 μmol, Eq: 0.01) and water (1.2 ml) were added. The reaction mixturewas heated to 70° C. and stirred for 16 h. The reaction mixture waspoured into saturated NaHCO₃ and extracted twice with Et₂O. The organiclayer was washed with brine, dried over Na₂SO₄ and concentrated invacuo. The crude material was purified by flash chromatography (silicagel, 60 g, 50% (60:10:1 DCM:MeOH:NH₄OH)/DCM) to give tert-butyl3-(6-aminopyridin-3-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (1.03 g,54%). LC/MS-ESI observed [M+H]⁺ 262.

Step 3

tert-Butyl 3-(6-aminopyridin-3-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate(1.5 g, 5.74 mmol, Eq: 1.00) was dissolved in MeOH (60 ml). The solutionwas purged with argon and then treated with palladium on activatedcarbon (Degussa) (6.11 mg, 57.4 μmol, Eq: 0.01). The suspension waspurged with hydrogen and stirred under a hydrogen atmosphere for 48 h.The reaction mixture was filtered through a 45 μm frit. The filtrate wasconcentrated in vacuo to give tert-butyl3-(6-aminopyridin-3-yl)pyrrolidine-1-carboxylate (1.63 g) Theenantiomers were separated using chiral SFC HPLC.

Prep Conditions

Prep Column: DAICEL AD 2×25 Oven Temp: 40° C.

Modifier: MeOH Modifier %:15

Flow rate: 70 mL Compound weight: 1610 mg

Solubility: Good in MeOH Solubility: 40 mg/mL

Amount of Injection: 10 mg Volume of Injection: 0.3 mL

Wavelength: 220 nM Method of Collection: Forced Time Window

Cycle Time: 6 min Number of Runs: 161

The (S)-3-(6-Amino-pyridin-3-yl)-pyrrolidine-1-carboxylic acidtert-butyl ester (307 mg, 20%) and(R)-3-(6-Amino-pyridin-3-yl)-pyrrolidine-1-carboxylic acid tert-butylester (399 mg, 26%) enantiomers were obtained. LC/MS-ESI observed [M+H]⁺264 for both enantiomers.

Step 4

(S)-tert-Butyl 3-(6-aminopyridin-3-yl)pyrrolidine-1-carboxylate (307 mg,1.17 mmol, Eq: 1.00) and 4-bromo-6-chloro-2-methylpyridazin-3(2H)-one(313 mg, 1.4 mmol, Eq: 1.20) were combined with4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (101 mg, 175 μmol, eq:0.15), cesium carbonate (1.14 g, 3.5 mmol, eq: 3) andtris(dibenzylideneacetone)dipalladium(0) (53.4 mg, 58.3 μmol, Eq: 0.05)in dioxane (8.0 ml). The solution was degassed with Ar. The reactionmixture heated at 100° C. for 18 h. The solution was cooled to roomtemperature and diluted with 100 ml DCM. The organic layer was washedwith water, and then dried over MgSO₄. Concentrated in vacuo. The crudematerial was purified by flash chromatography (silica gel, 24 g, 50% to100% EtOAc/Hex gradient) to give (S)-tert-butyl3-(6-(6-chloro-2-methyl-3-oxo-2,3-dihydropyridazin-4-ylamino)pyridin-3-yl)pyrrolidine-1-carboxylate(456 mg, 96%).

LC/MS-ESI observed [M+H]⁺ 405.

Step 5

(S)-tert-Butyl3-(6-(6-chloro-2-methyl-3-oxo-2,3-dihydropyridazin-4-ylamino)pyridin-3-yl)pyrrolidine-1-carboxylate(456 mg, 1.12 mmol, Eq: 1.00) was dissolved in a mix of formic acid(20.0 ml) and formaldehyde, 37% (40 ml). The reaction mixture stirred at70° C. for 18 h. The solution was cooled to room temperature and waterwas added. The aqueous solution was extracted once with DCM. The aqueouslayer was Brought to pH=14 with solid K₂CO₃. A solid formed and wasfiltered to give(S)-6-chloro-2-methyl-4-(5-(1-methylpyrrolidin-3-yl)pyridin-2-ylamino)pyridazin-3(2H)-one(408 mg, quantitative yield). LC/MS-ESI observed [M+H]⁺ 320.

Step 6

In a 50 mL test tube,(S)-6-chloro-2-methyl-4-(5-(1-methylpyrrolidin-3-yl)pyridin-2-ylamino)pyridazin-3(2H)-one(100 mg, 313 μmol, Eq: 1.00) and potassium(2-(acetoxymethyl)-3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)phenyl)trifluoroborate(163 mg, 344 μmol, Eq: 1.1) were combined with BuOH (4.0 ml) to give aorange solution. Water (1.0 ml) was added. X-PHOS (14.9 mg, 31.3 μmol,Eq: 0.10) and potassium phosphate tribasic (133 mg, 625 μmol, eq: 2.0)were added. Bis(dibenzylideneacetone)palladium (8.99 mg, 15.6 μmol, eq:0.05) was added. The reaction mixture was purged with argon, then heatedin a oil bath at 100° C. for 18 hours. The reaction mixture was cooledto room temperature, then poured into 75 mL H₂O and extracted withEtOAc. The organic layer was washed with brine and then dried overMgSO₄. Concentrated in vacuo. The crude material was purified by flashchromatography (silica gel, 12 g, 50% to 100% (60:10:1DCM:MeOH:NH₄OH)/DCM) gradient) to give a mixture of(S)-2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(1-methyl-5-(5-(1-methylpyrrolidin-3-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridazin-3-yl)benzylacetate and6-tert-butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-((S)-1-methyl-pyrrolidin-3-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one(105 mg total, 52% overall). LC/MS-ESI observed [M+H]⁺ 652 and 610.

Step 7

To a mixture of(S)-2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(1-methyl-5-(5-(1-methylpyrrolidin-3-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridazin-3-yl)benzylacetate and6-tert-butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-((S)-1-methyl-pyrrolidin-3-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one(105 mg, 161 μmol, Eq: 1.00) in MeOH (10 ml) was added potassiumcarbonate (44.5 mg, 322 μmol, Eq: 2.0). The reaction mixture stirred at40° C. for 1.5 h. The mixture was cooled to room temperature and dilutedwith DCM/water. The layers were separated. The aqueous layer wasextracted once with DCM. The organic layers were combined and dried overNa₂SO₄. Concentrated in vacuo. The resulting solid was triturated withEt₂O to give6-tert-butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-((S)-1-methyl-pyrrolidin-3-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one(80 mg, 81%). LC/MS-ESI observed [M+H]⁺ 610. 1H NMR in CDCl₃ isconsistent with desired product.

Preparation of I-33 Example 336-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-((R)-1-methyl-pyrrolidin-3-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one

Step 1

This reaction was carried out under similar conditions to thosedescribed above in step 4 of the preparation of Example 32.(R)-tert-butyl3-(6-(6-chloro-2-methyl-3-oxo-2,3-dihydropyridazin-4-ylamino)pyridin-3-yl)pyrrolidine-1-carboxylate(555 mg, 90%). LC/MS-ESI observed [M+H]⁺ 405.

Step 2

This reaction was carried out under similar conditions to thosedescribed above in step 5 of the preparation of Example 32.(R)-6-chloro-2-methyl-4-(5-(1-methylpyrrolidin-3-yl)pyridin-2-ylamino)pyridazin-3(2H)-one(807 mg, quantitative). LC/MS-ESI observed [M+H]⁺ 320.

Step 3

This reaction was carried out under similar conditions to thosedescribed above in step 6 of the preparation of Example 32 resulting ina mixture of(R)-2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(1-methyl-5-(5-(1-methylpyrrolidin-3-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridazin-3-yl)benzylacetate and6-tert-butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-((R)-1-methyl-pyrrolidin-3-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one(135 mg total, 66% over all). LC/MS-ESI observed [M+H]⁺ 652 and 610.

Step 4

This reaction was carried out under similar conditions to thosedescribed above in step 7 of the preparation of Example 32.6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-((R)-1-methyl-pyrrolidin-3-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one(124 mg, 98%). LC/MS-ESI observed [M+H]⁺ 610. ¹H NMR in CDCl₃ isconsistent with desired product.

Preparation of I-34 Step 1. Preparation of4-Methyl-5′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl

In a 15 mL argon dried microwave reaction vial, was addedbromonitropyrazine (300 mg, 1.47 mmol., Eq: 1.00) and K₂CO₃ (264 mg,1.91 mmol., Eq: 1.3) under argon to give a light yellow slurry.N-methylpiperazine (192 mg, 212 μl, 1.91 mmol, Eq: 1.3) was addeddropwise and the reaction mixture became an orange yellow thick slurry.Heated to 70° C. in an oil bath for 1.5 hrs then stirred at roomtemperature overnight. The reaction mixture was diluted with dioxane (10mL), filtered through a fitted funnel and washed with DCM (10 mL). Thecombined filtrate and washes were concentrated to dryness to give ayellow solid (328 mg, yield 89%) which was used directly in the nextstep.

Step 2. Preparation of4-Methyl-3,4,5,6-tetrahydro-2H-[1,2]bipyrazinyl-5′-ylamine

2-(4-methylpiperazin-1-yl)-5-nitropyrazine (328 mg, 1.47 mmol) wasdissolved in MeOH (15 ml) at room temperature. Pd/C (10%) (50 mg) wasadded while the reaction mixture was stirred. The reaction mixture wasplaced under a H₂ balloon and stirred at rt for 1.5 hrs. The reactionmixture was filtered through celite and washed with MeOH (30 mL). Thefiltrate was stripped and dried under vacuum after azeotroping withtoluene twice to give a light brown gummy material (280 mg, yield 89%).

Step 3. Preparation of6-Chloro-2-methyl-4-(4-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-ylamino)-2H-pyridazin-3-one

In a 15 mL microwave reaction vial (dried over heat and argon) was addeda solution of aminopyrazine (280 mg, 1.45 mmol, Eq: 1.00) in dioxane (7ml) under argon bubbling. To this solution was addedbromochloropyridazinone (421 mg, 1.88 mmol, Eq: 1.3), Cs₂CO3 (1.3 g,3.99 mmol, Eq: 2.75), xantphos (126 mg, 217 μmol, Eq: 0.15) andbis(dibenzylideneacetone)palladium (62.5 mg, 109 μmol, Eq: 0.075). Thereaction was sealed and heated in oil bath at 105° C. (bath temp) for 7hrs then stirred at room temperature overnight. The reaction wasfiltered through a fitted funnel and washed with dioxane (20 mL). Thecombined filtrate and washes were concentrated to dryness. The residuewas taken up in 10% MeOH in DCM and purified by prep TLC (9×) in 10%(10% NH₄OH in MeOH) in DCM. to afford 71 mg (15%) of a yellow solid.

Example 34 Step 4. Preparation of6-tert-Butyl-8-fluoro-2-{2-hydroxymethyl-3-[1-methyl-5-(4-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-ylamino)-6-oxo-1,6-dihydro-pyridazin-3-yl]-phenyl}-2H-phthalazin-1-one

To a 15 mL microwave reaction vial was added6-chloro-2-methyl-4-(4-methyl-3,4,5,6-tetrahydro-2H-[1,2]bipyrazinyl-5′-ylamino)-2H-pyridazin-3-one(71 mg, 211 μmol, Eq: 1.00) in 7 mL n-butanol and 1.4 mL water. Argonwas bubbled through the suspension. To the slurry was added potassium(2-(acetoxymethyl)-3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)phenyl)trifluoroborate(149 mg, 211 μmol, Eq: 1.00), then X-PHOS (15.1 mg, 31.7 μmol, Eq: 0.15)with stirring. To this mixture was addedbis(dibenzylideneacetone)palladium (9.12 mg, 15.9 μmol, Eq: 0.075). Thetube was sealed and heated at 110° C. (bath temp) for 3 hrs then cooledto room temperature. A solution of NaOH (84 mg, 2.11 mmol, 10 eq) inwater (1.5 mL) was added and the reaction was stirred for 3 days.

The layers were separated and the aqueous layer was extracted with EtOAcand combined with the previous organic layer. The combined extracts wereconcentrated to 4-5 mL. The crude material was purified by preparativeTLC(11×) with 11% (10% NH₄OH in MeOH) in 1/1 (EtOAc/Heptane) to give 50mg (36%) of a light yellow solid. Mp: 235-240° C. ¹H NMR (300 MHz,CHLOROFORM-d) 1.43 (s, 9H), 2.36 (s, 3H), 2.51 (t, J=5.0 Hz, 4H), 3.50(t, J=5.0 Hz, 4H), 3.90 (s, 3H), 3.95 (t, J=6.2 Hz, 1H), 4.40 (d, J=6.2Hz, 2H), 7.43-7.65 (m, 5H), 7.88 (d, J=1.13 Hz, 1H), 8.03 (d, J=1.51 Hz,1H), 8.15 (s, 1H), 8.25 (s, 1H), 8.30 (d, J=2.5, 1 H).

LCMS (ES): 626 (M+H), RT=1.94 min.

Preparation of I-35 Step 1. Preparation of(5-Cyclobutylaminomethyl-pyrazin-2-yl)-carbamic acid tert-butyl ester

In a dried 100 mL round bottom flask was added cyclobutylamine (740 mg,889 μL, 10.4 mmol, Eq: 3), K₂CO3 (480 mg, 3.47 mmol, Eq: 1.00) and THFat rt. under argon. To the mixture was added a solution of(5-Bromomethyl-pyrazin-2-yl)-carbamic acid tert-butyl ester (1 g, 3.47mmol, Eq: 1.00) in THF dropwise. The resulting reaction mixture wasstirred vigorously at room temperature under argon overnight. Thereaction was concentrated, diluted with water/DCM and extracted with DCM(2×30 mL). Combined organic extracts were concentrated to give a solid.The crude product was purified by LC chromatography (50 g sphericalsilica column) eluting with 5 to 10% MeOH in 1/1 EtOAc/Hex to afford 348mg (36%) of the title compound as a white solid.

Step 2. Preparation of 5-Cyclobutylaminomethyl-pyrazin-2-ylamine

In a 15 mL microwave tube was dissolved tert-butyl5-((cyclobutylamino)methyl)pyrazin-2-ylcarbamate (330 mg, 1.19 mmol, Eq:1.00) in 2,2,2-trifluoroethanol (119 mg, 12 ml, 1.19 mmol, Eq: 1.00) andthe resulting mixture was heated in seal tube at 150° C. for 3 hrs. Thecrude reaction mixture was concentrated in vacuo, treated with MeOH andre-concentrated to remove residual trifluoroethanol. The material wasazeotroped with toluene to afford 200 mg (95%) of the title compound.

Step 3. Preparation of6-Chloro-4-(5-cyclobutylaminomethyl-pyrazin-2-ylamino)-2-methyl-2H-pyridazin-3-one

In a 15 mL microwave reaction vial was added a solution of5-((cyclobutylamino)methyl)pyrazin-2-amine (280 mg, 1.57 mmol, Eq: 1.00)in dioxane (7 ml) under argon bubbling. To the solution was added4-bromo-6-chloro-2-methylpyridazin-3(2H)-one (456 mg, 2.04 mmol, Eq:1.3), Cs₂CO₃ (1.3 g, 3.99 mmol, Eq: 2.54), xantphos (136 mg, 236 mmol,Eq: 0.15) and bis(dibenzylideneacetone)palladium (67.7 mg, 118 μmol, Eq:0.075). The reaction tube was sealed and heated in oil bath at 105° C.(bath temp) for 7 hrs then stirred at room temperature overnight. Thecrude reaction mixture was filtered and the solid was washed withdioxane (20 mL) and DCM (5 mL). The combined filtrate and washes wereconcentrated and absorbed on silica gel. The mixture was purified by LCchromatography (silica gel, 60 g) and eluted with 0-10% (10% NH₄OH inMeOH) in ( 1/1) EtOAc/Heptane to afford 197 mg (39%) of the titlecompound.

Example 35 Step 4. Preparation of6-tert-Butyl-2-{3-[5-(5-cyclobutylaminomethyl-pyrazin-2-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl]-2-hydroxymethyl-phenyl}-8-fluoro-2H-phthalazin-1-one

In a 15 mL microwave reaction vial was added6-chloro-4-(5-cyclobutylaminomethyl-pyrazin-2-ylamino)-2-methyl-2H-pyridazin-3-one(71 mg, 221 μmol, Eq: 1.00) in 7 mL n-butanol and 1.4 mL water. Argonwas bubbled through the reaction mixture. To the reaction was addedacetic acid2-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzylester (218 mg, 309 μmol, Eq: 1.39), potassium phosphate tribasic (103mg, 487 μmol then X-PHOS (15.8 mg, 33.2 μmol, Eq: 0.15). The mixture waspurged with argon and (dibenzylideneacetone)palladium (9.55 mg, 16.6μmol, Eq: 0.075) was added. The tube was sealed and heated at 110° C.(bath temp) for 3 hrs. The reaction mixture was allowed to cool to roomtemperature, a solution of NaOH (189 mg) in water (1.5 mL) was added andthe mixture was stirred in an oil bath at 37° C. for 3 hrs. The crudereaction mixture was diluted with water (10 mL) and extracted withdichloromethane (3×10 mL). The organic phase was concentrated andchromatographed on silica gel eluting with 5-10% (10% in NH₄OH in MeOH)in ( 1/1) EtOAc/n-heptane to give a pure fraction (pale yellow) andmixed fractions (yellow). The pure fraction was concentrated anddissolved in DCM. Methanol was added to make a 10% solvent mixture ofMeOH in DCM. Heptane was added which resulted in immediate precipitationof solid. The suspension was allowed to sit at room temperatureovernight and the resultant solid was filtered, washed with n-heptaneand dried to afford 35 mg (25%) of the title compound as an off-whitesolid. mp: 163-167° C.

¹H NMR (300 MHz, CHLOROFORM-d) 1.43 (s, 9H), 1.70-1.72 (m, 4H),2.19-2.22 (m, 2H), 3.28-3.31 (m, 1H), 3.75 (t, J=6.2 Hz, 1H), 3.80 (s,2H), 3.89 (s, 3H), 4.40 (d, J=6.2 Hz, 2H), 7.43-7.65 (m, 5H), 8.28 (d,J=1.13 Hz, 1H), 8.30 (d, J=2.5, 1H), 8.36 (d, J=1.51 Hz, 1H), 8.40 (s,1H), 8.60 (s, 1H). LCMS (ES): 611 (M+H), RT=2.511 min.

Preparation of I-36 Step 1. Preparation ofDimethyl-[2-(5-nitro-pyrazin-2-yloxy)-ethyl]-amine

To a 100 ml dried round bottom flask was added bromonitropyrazine (300mg, 1.47 mmol, Eq: 1.00) and CH₃CN (10 ml). To the mixture was addedK₂CO₃ (203 mg, 1.47 mmol, Eq: 1.00) under argon to afford a light yellowslurry. To the slurry was added N,N-dimethylaminothanol (131 mg, 148 μl,1.47 mmol, Eq: 1.00) dropwise. The reaction became an orange slurry andwas stirred at room temperature overnight. The reaction mixture wasfiltered and the filter cake was washed with CH₃CN (3×20 mL). Thecombined filtrate and washes were concentrated in vacuo and purified bycolumn chromatography eluting with 5-10% (10% NH₄OH in MeOH) in 1/1EtOAc/Hex eluent to afford 270 mg (87%) of the title compound.

Step 2. Preparation of 5-(2-Dimethylamino-ethoxy)-pyrazin-2-ylamine

In a 500 mL round bottomed flask containingN,N-dimethyl-2-(5-nitropyrazin-2-yloxy)ethanamine (270 mg, 1.27 mmol,Eq: 1.00) was added MeOH (20 ml) and 10% Pd/C (60 mg). The reaction wasstirred under a hydrogen atmosphere for 2 hrs then stored at 0° C. for 3days. The reaction mixture was filtered through celite and washed withMeOH. The filtrate was concentrated in vacuo to afford 209 mg, (90%) ofthe title compound as a gummy solid.

Step 3. Preparation of6-Chloro-4-[5-(2-dimethylamino-ethoxy)-pyrazin-2-ylamino]-2-methyl2H-pyridazin-3-one

In a 15 mL microwave reaction vial was added a solution of5-(2-(dimethylamino)ethoxy)pyrazin-2-amine (190 mg, 1.04 mmol, Eq: 1.00)in dioxane (7 ml) under argon.4-bromo-6-chloro-2-methylpyridazin-3(2H)-one (303 mg, 1.36 mmol, Eq:1.3), Cs₂CO₃ (1.02 g, 3.13 mmol, Eq: 3), xantphos (90.5 mg, 156 μmol,Eq: 0.15) and bis(dibenzylideneacetone)palladium (45.0 mg, 78.2 μmol,Eq: 0.075) were added and the reaction tube was heated in an oil bath at105° C. (bath temp) for 7 hrs followed by stirring at room temperatureovernight. The reaction mixture was filtered and the solid was washedwith dioxane (20 mL) and DCM (5 mL). The combined filtrate and washeswas concentrated. The residue was purified by LC chromatography elutingwith 0-10% (10% NH₄OH in MeOH) in ( 1/1) EtOAc/heptane to afford 339 mg(67%) of the title compound.

Example 36 Step 4. Preparation of6-tert-Butyl-2-(3-{5-[5-(2-dimethylamino-ethoxy)-pyrazin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-2-hydroxymethyl-phenyl)-8-fluoro-2H-phthalazin-1-one

In a 15 mL microwave reaction vial was added6-chloro-4-[5-(2-dimethylamino-ethoxy)-pyrazin-2-ylamino]-2-methyl2H-pyridazin-3-one(89 mg, 274 μmol, Eq: 1.00) in 7 mL n-butanol and 1.4 mL water. To thesolution was added potassium phosphate tribasic (128 mg, 603 μmol),X-PHOS (19.6 mg, 41.1 μmol, Eq: 0.15) and acetic acid2-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzylester (279 mg, 395 μmol, Eq: 1.44) with stirring and bubbling of argon.To this mixture was added bis(dibenzylideneacetone)palladium (11.8 mg,20.6 μmol, Eq: 0.075) and the reaction was heated at 110° C. for 3 hrs.The reaction was cooled to room temperature and treated with a solutionof NaOH (220 mg) in water (1.5 mL). The resultant mixture was stirred atroom temperature for 20 h. The reaction mixture was diluted with DCM (50mL) and water (50 mL). The organic phase was separated, washed withwater (30 mL) and concentrated. The residue was purified on silica gelwith 0-10% (10% NH₄OH in MeOH) in ( 1/1) EtOAc/Hex. The pure fractionswere concentrated and dissolved in DCM. Heptane was added to precipitatethe product. The liquid was decanted off to afford 81 mg (46%) of thetitle compound as an off white solid. mp: 185-190° C.

¹H NMR (300 MHz, CHLOROFORM-d) 1.43 (s, 9H), 2.37 (s, 6H), 2.74 (t,J=5.5 Hz, 2H), 3.85 (t, J=6.2 Hz, 1H), 3.92 (s, 3H), 4.40 (m, 4H),7.43-7.65 (m, 5H), 7.95 (d, J=1.13 Hz, 1H), 8.06 (d, J=1.51, 1H),8.26-8.35 (m, 3H). LCMS (ES): 615 (M+H), RT=1.925 min.

Example 37 Preparation of6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methyl-piperazin-1-ylmethyl)-pyrazin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one

Preparation by a similar procedure to Example 35, except substitutingmethylpiperazine for cyclobutylamine in step 1, afforded 107 mg (53%) ofthe title compound as a white solid after LC chromatography andsubsequent recrystallization from DCM/heptane. mp: 215-218° C. ¹H NMR(300 MHz, CHLOROFORM-d) 1.43 (s, 9H), 2.30 (s, 3H), 2.40-2.61 (m, 8H),3.67 (s, 3H), 3.80 (t, J=6.2 Hz, 1H), 3.93 (s, 3H), 4.45 (d, J=6.2 Hz,2H), 7.43-7.65 (m, 5H), 8.30 (d, J=2.5, 1 H), 8.33 (d, J=1.13 Hz, 1H),8.36 (d, J=1.51 Hz, 1H), 8.43 (s, 1H), 8.65 (s, 1H). LCMS (ES): 640(M+H), RT=2.104 min.

Example 38 Preparation of6-tert-Butyl-2-(3-{5-[5-(2-dimethylamino-1,1-dimethyl-ethoxy)-pyrazin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-2-hydroxymethyl-phenyl)-8-fluoro-2H-phthalazin-1-one

Preparation by a similar procedure to Example 36, except substituting1-dimethylamino-2-methyl-propan-2-ol for N,N-dimethylaminothanol in step1, afforded 100 mg (50%) of the title compound. mp: 235-240° C. ¹H NMR(300 MHz, CHLOROFORM-d) 1.43 (s, 9H), 1.56 (s, 6H), 2.37 (s, 6H), 3.80(t, J=6.2 Hz, 1H), 3.90 (s, 3H), 4.45 (d, J=6.2 Hz, 2H), 7.43-7.65 (m,5H), 7.89 (d, J=1.13 Hz, 1H), 7.96 (d, J=1.51 Hz, 1H), 8.24 (s, 1H),8.30 (d, J=2.5, 1 H), 8.35 (s, 1H). LCMS (ES): 643 (M+H), RT=2.516 min.

Preparation of I-39 Step 1. Preparation of[2-(6-Bromo-pyridazin-3-yloxy)-2-methyl-propyl]-dimethyl-amine

In a 100 mL round bottom flask was added1-(dimethylamino)-2-methylpropan-2-ol (1.48 g, 12.6 mmol, Eq: 1.5), THFand 3,6-dibromopyridazine (2 g, 8.41 mmol, Eq: 1.00). The flask wascooled to 0° C. followed by addition of NaH (572 mg, 14.3 mmol, Eq: 1.7)in one portion. The turbid reaction mixture was allowed to warm to roomtemperature and was stirred at room temperature overnight. The resultantblack reaction mixture was absorbed onto silica gel and purified by LCchromatography eluting with 0-5% MeOH in 1/1 EtOAc/Hex to afford 1.5 g(65%) of the title compound.

Step 2. Preparation ofBenzhydrylidene-[6-(2-dimethylamino-1,1-dimethyl-ethoxy)-pyridazin-3-yl]-amine

In a 15 ml microwave reaction vial was added2-(6-bromopyridazin-3-yloxy)-N,N,2-trimethylpropan-1-amine (500 mg, 1.82mmol, Eq: 1.00) and toluene (7 ml). Argon was bubbled through themixture. To this mixture was added(R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (170 mg, 274 μmol,Eq: 0.15), Cs₂CO₃ (2.38 g, 7.3 mmol, Eq: 4) and Pd(OAc)₂ (30.7 mg, 137μmol, Eq: 0.075). The reaction was heated at 120° C. in an oil bath for7 hrs followed by stirring at room temperature overnight. The redsolution was decanted away from the grey solid. The solid was washedwith EtOAc and the combined organic phases were concentrated in vacuo.The residue was purified by LC chromatography eluting with 1/1EtOAc/Hexane to afford 380 mg (56%) of the title compound as an orangeoil.

Step 3. Preparation of6-(2-Dimethylamino-1,1-dimethyl-ethoxy)-pyridazin-3-ylamine

In a 10 mL pear shape flask was added6-(1-(dimethylamino)-2-methylpropan-2-yloxy)-N-(diphenylmethylene)pyridazin-3-amine(200 mg, 534 μmol, Eq: 1.00) and MeOH (5.34 ml). To the mixture wasadded hydroxylamine hydrochloride (66.8 mg, 961 μmol, Eq: 1.8) andsodium acetate (105 mg, 1.28 mmol, Eq: 2.4). The mixture was stirred atroom temperature for 25 min. The reaction mixture was absorbed on tosilica and purified by LC chromatography eluting with 0-5% (10% NH₄OH inMeOH) in 1/1 EtOAc/Hexane to afford 110 mg (98%) of the title compound.

Step 4. Preparation of6-Chloro-4-[6-(2-dimethylamino-1,1-dimethyl-ethoxy)-pyridazin-3-ylamino]-2-methyl-2H-pyridazin-3-one

In a 15 mL microwave reaction vial was added a solution of6-(1-(dimethylamino)-2-methylpropan-2-yloxy)pyridazin-3-amine (110 mg,523 μmol, Eq: 1.00) in dioxane (5 ml) under argon. To the solution wasadded 4-bromo-6-chloro-2-methylpyridazin-3(2H)-one (152 mg, 680 μmol,Eq: 1.3), Cs₂CO₃ (511 mg, 1.57 mmol, Eq: 3), xantphos (45.4 mg, 78.5μmol, Eq: 0.15) and bis(dibenzylideneacetone)palladium (22.6 mg, 39.2μmol, Eq: 0.075). The reaction tube was sealed and heated in oil bath at110° C. (bath temp) for 7 hrs, then was cooled to room temperature andstirred overnight. The reaction mixture was filtered and the solid waswashed with THF (20 mL). The combined filtrate and washes wereconcentrated in vacuo. The reaction mixture was absorbed on to silicaand purified by LC chromatography eluting with 0-5% (MeOH) in 1/1EtOAc/heptane to afford 130 mg (70%) of the title compound.

Example 39 Step 5. Preparation of6-tert-Butyl-2-(3-{5-[6-(2-dimethylamino-1,1-dimethyl-ethoxy)-pyridazin-3-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-2-hydroxymethyl-phenyl)-8-fluoro-2H-phthalazin-1-one

In a 15 mL microwave reaction vial was added6-chloro-4-(6-(1-(dimethylamino)-2-methylpropan-2-yloxy)pyridazin-3-ylamino)-2-methylpyridazin-3(2H)-one(75 mg, 213 μmol, Eq: 1.00), n-BuOH (6 ml) and water (1.5 ml). To themixture was added potassium(2-(acetoxymethyl)-3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)phenyl)trifluoroborate(101 mg, 213 μmol, Eq: 1.00) under argon. X-PHOS (10.6 μA, 31.9 μmol,Eq: 0.15) and potassium phosphate tribasic (99.3 mg, 468 μmol, Eq: 2.2)was added followed by bis(dibenzylideneacetone)palladium (9.17 mg, 15.9μmol, Eq: 0.075). The tube was sealed under argon and heated in an oilbath at 115° C. for 3 hrs then stirred at room temperature overnight. Tothis mixture was added 100 mg NaOH in 1 mL distilled water. The mixturewas warmed in an oil bath at 50° C. for 3 hrs then stirred at roomtemperature overnight. The crude reaction mixture was diluted with water(20 mL) and extracted with DCM (2×30 mL). The combined organic extractswere concentrated and absorbed onto silica gel. The crude material waspurified by LC chromatography eluting with 0-5% (10% NH₄OH in MeOH) in1/1 EtOAc/heptane to afford 67 mg (47%) of the title compound as a paleyellow solid. Mp: 140-145° C. ¹H NMR (300 MHz, CHLOROFORM-d) 1.43 (s,9H), 1.67 (s, 6H), 2.37 (s, 6H), 2.80 (s, 2H), 3.80 (t, J=6.2 Hz, 1H),3.92 (s, 3H), 4.45 (d, J=6.2 Hz, 2H), 6.90 (d, J=9 Hz, 1H), 7.10 (d, J=9Hz, 1H), 7.43-7.65 (m, 5H), 8.20 (s, 1H), 8.28 (d, J=2.5, 1H), 8.55 (s,1H). LCMS (ES): 643(M+H), RT=1.942 min.

Preparation of I-40 Step 1. Preparation of6-(1-Methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-pyridazin-3-ylamine

In a 15 mL microwave reaction vial was added potassium phosphatetribasic (1.43 g, 6.74 mmol), 6-bromopyridazin-3-amine (335 mg, 1.93mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridiniumchloride (500 mg, 1.93 mmol), X-PHOS (138 mg, 289 μmol) andbis(dibenzylideneacetone)palladium (83 mg, 144 μmol) in 7 mL n-butanoland 1.4 mL H₂O. The tube was sealed under argon and heated at 115° C. inoil bath for 3 hrs then stirred at room temperature overnight. Thephases were separated and the aqueous was extracted with EtOAc.(10 ml).Water (20 mL) was added to the residual aqueous phase and was extractedwith DCM (3×10 mL). The extracts were combined with the EtOAc organicphase. The resultant solution was absorbed onto silica gel and purifiedby LC chromatography eluting with 0-10% (10% NH₄OH in MeOH) in 1/1EtOAc/hexane to afford 300 mg (82%) of the title compound.

Step 2. Preparation of 6-(1-Methyl-piperidin-4-yl)-pyridazin-3-ylamine

6-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)pyridazin-3-amine (300 mg,1.58 mmol, Eq: 1.00) was dissolved in EtOH (30 ml). The reactionsolution was hydrogenated in an H-Cube apparatus (60 psi) at roomtemperature with Pd/C by running mixture through the cycle twice untilreaction was complete as determined by tlc. The solvent was removed invacuo to afford 270 mg (89%) of the title compound.

Step 3. Preparation of6-Chloro-2-methyl-4-[6-(1-methyl-piperidin-4-yl)-pyridazin-3-ylamino]-2H-pyridazin-3-one

In a 15 mL reaction vial was added a solution of6-(1-methylpiperidin-4-yl)pyridazin-3-amine (190 mg, 988 μmol, Eq: 1.00)in dioxane (7 ml). Argon was bubbled through the solution and6-chloro-2-methyl-4-(6-(1-methylpiperidin-4-yl)pyridazin-3-ylamino)pyridazin-3(2H)-one(160 mg, 430 μmol, 43.5% yield) and Cs2CO3 (966 mg, 2.96 mmol, Eq: 3)were added. To this mixture was added xantphos (86 mg, 148 μmol, Eq:0.15) and bis(dibenzylideneacetone)palladium (42.6 mg, 74.1 μmol, Eq:0.075). The tube was sealed under argon and heated in an oil bath at115° C. (bath temp) for 7 hrs then stirred at room temperatureovernight. The reaction was diluted with THF (10 mL), filtered and thesolid was washed with THF (3×10 mL). The combined washes wereconcentrated and purified by solid loading on 40 g silica gel column andeluting with 10% (10% NH₄OH in MeOH) in 1/1 EtOAc/hexane to afford 160mg (44%) of the title compound as an orange solid.

Example 40 Step 3. Preparation of6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[6-(1-methyl-piperidin-4-yl)-pyridazin-3-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one

In a 15 mL microwave reaction vial was added6-chloro-2-methyl-4-(6-(1-methylpiperidin-4-yl)pyridazin-3-ylamino)pyridazin-3(2H)-one(160 mg, 478 μmol, Eq: 1.00), potassium(2-(acetoxymethyl)-3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)phenyl)trifluoroborate(272 mg, 573 μmol, Eq: 1.2) with n-BuOH (7.5 ml) and water (1.5 ml).Argon was bubbled through the solution for 5 min. To the mixture wasadded X-PHOS (34.2 mg, 71.7 μmol, Eq: 0.15) and potassium phosphatetribasic (304 mg, 1.43 mmol, Eq: 3). Argon was bubbled through themixture for 5 min. To this mixture was addedbis(dibenzylideneacetone)palladium (20.6 mg, 35.8 μmol, Eq: 0.075). Thetube was sealed under argon and heated in oil bath at 110° C. for 3 hrs.The mixture was cooled to room temperature and treated with a solutionof 220 mg NaOH in 1.5 mL water dropwise. The resultant mixture washeated in an oil bath at 50° C. for 3 hrs with strong stirring. Thereaction mixture was diluted with water (20 mL) and extracted with DCM(3×30 mL). The combined extracts were concentrated and purified by solidloading on a 40 g silica gel column and eluting with 5-10% (10% NH₄OH inMeOH) in 1/1 EtOAc/hexane to afford 61 mg (20%) of the title compound asa yellow solid. mp: 260-265° C. ¹H NMR (300 MHz, CHLOROFORM-d) 1.43 (s,9H), 1.80-2.20 (m, 6H), 2.37 (s, 3H), 2.90-3.07 (m, 3H), 3.85 (t, J=6.2Hz, 1H), 3.92 (s, 3H), 4.45 (d, J=6.2 Hz, 2H), 7.15 (d, J=9 Hz, 1H),7.35 (d, J=9 Hz, 1H), 7.43-7.65 (m, 5H), 8.28 (d, J=2.5, 1H), 8.32 (s, 1H), 8.78 (s, 1H). LCMS (ES): 625 (M+H), RT=2.21 min.

Preparation of I-41

Step 1

1-(6-Chloro-pyridin-3-ylmethyl)-4-methyl-piperazine:6-Chloronicotinaldehyde (10 g, 70.6 mmol, Eq: 1.00) was suspended in 700ml DCM. 1-Methylpiperazine (8.84 g, 88.3 mmol, Eq: 1.25) and acetic acid(8.48 g, 8.09 ml, 141 mmol, Eq: 2.0) were added. Sodiumtriacetoxyborohydride (22.5 g, 106 mmol, Eq: 1.5) was added in portionsover several minutes. The reaction mixture stirred at room temperature.After 3.5 hrs, there was no sign of starting material. LCMS showedproduct plus a little reduced starting material. Water was added,followed by DCM and the layers were separated. The DCM layer was washedwith saturated ammonium chloride and the aqueous layer was combined withthe initial aqueous layer. The aqueous extractions were bacidified with1M NaOH. The resulting aqueous layer was extracted 3 times with DCM, andthen dried, and concentrated to give 13.5 grams of a light yellow oil(84.7%) which was used without further purification.

Step 2

5-(4-Methyl-piperazin-1-ylmethyl)-pyridin-2-ylamine: To a sealed tubeunder nitrogen was added1-((6-chloropyridin-3-ylmethyl)-4-methylpiperazine (13.5 g, 59.8 mmol,Eq:1.00), 2-(dicyclohexylphosphino)biphenyl (4.19 g, 12.0 mmol,Eq:0.20), tris(dibenzylideneacetone)-dipalladium (0) (5.48 g, 5.98 mmol,Eq: 0.10), and lithium bis(trimethylsilyl)amide, 150 ml of a 1.0Msolution in THF. An additional 150 ml THF was added. The flask wasdegassed with argon. The flask was capped and the reaction heated at100° C. overnight. 3M HCl was added along with DCM to the material andthe layers were separated. The aqueous layer was bacidified with 3MNaOH. The aqueous layer was then extracted 3 times with DCM to provide3.2 g (25.9%) of a yellow powder which was used without furtherpurification.

Step 3

6-Chloro-2-methyl-4-[5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-ylamino]-2H-pyridazin-3-one:5-((4-Methylpiperazin-1-yl)methyl)pyridin-2-amine (3.2 g, 15.5 mmol,Eq:1.00), 4-bromo-6-chloro-2-methylpyridazin-3(2H)-one (3.64 g, 16.3mmol, Eq:1.05), xantphos (1.35 g, 2.33 mmol, Eq: 0.15)tris(dibenzylideneacetone)dipalladium (0) (1.07 g, 1.16 mmol, Eq: 0.075)and cesium carbonate (15.2 g, 46.5 mmol, Eq: 3.00) were added to asealed tube under nitrogen. Dioxane (103 ml) was added and the solutionwas degassed with nitrogen. The tube was capped and heated at 110° C.overnight. The reaction mixture was filtered through celite and the cakewas washed with DCM. 1M HCl was added to and the layers were separated.The aqueous layer was basified with 2M NaOH and extracted several timeswith DCM. Most of the solvent was evaporated and the residue wastriturated with ether. The solid that formed was filtered and dried togive 2.75 g (50.8%) of product which was used without furtherpurification.

Step 4

Acetic acid2-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-6-{1-methyl-5-[5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-benzylester:6-Chloro-2-methyl-4-(5-((4-methylpiperazin-1-yl)methyl)pyridin-2-ylamino)pyridazin-3(2H)-one(3.1 g, 8.89 mmol, Eq: 1.00),2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate (7.69 g, 15.6 mmol, Eq: 1.75), X-PHOS (424 mg, 0.89 mmol, Eq:0.10), bis(dibenzylideneacetone)palladium (255 mg, 0.44 mmol, Eq: 0.05)and tripotassium phosphate (4.72 g, 22.2 mmol, Eq: 2.50) were added to alarge microwave vial. The vial was capped and purged. N-butanol (35.5ml) and water (9 ml) were added and the vial was purged again andbackfilled with nitrogen. The reaction was heated in a sand bath at 115°C. for 2.5 hours. Water and DCM were added to the reaction and thelayers were separated. The organic layer was filtered through celite,concentrated, and purified by chromatography using a gradient of 0% to25% methanol in DCM. Fractions with and without the protecting groupwere combined to give a combined yield of 4.5 g (approximately 74%).

Example 41 Step 56-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one

Acetic acid2-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-6-{1-methyl-5-[5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-benzylester (4.5 g, 6.61 mmol, Eq: 1.00) and potassium carbonate (1.37 g, 9.92mmol, Eq: 1.50) were dissolved in methanol and heated at 40° C. for 1hour. The reaction was cooled to room temperature and water was addeddropwise. The reaction was stirred at room temperature overnight. Thesolid that formed was filtered, washed with water, and dried in a vacuumoven over the weekend to give 3.64 g (86.2%) of an off-white crystallinesolid. ¹H NMR (300 MHz, DMSO-d6) δ ppm 9.39 (s, 1H) 8.53 (s, 1H) 8.50(d, J=2.3 Hz, 1H) 8.15 (d, J=1.9 Hz, 1H) 7.86 (d, J=1.5 Hz, 1H) 7.74(dd, J=13.4, 1.7 Hz, 1H) 7.57-7.62 (m, 1H) 7.50-7.57 (m, 2H) 7.43-7.49(m, 2H) 4.52-4.61 (m, 1H) 4.40 (br. s., 2H) 3.77 (s, 3H) 3.36 (s, 2H)2.30 (br. s., 8H) 2.11 (s, 3H) 1.37 (s, 9H). MS: (M+H)⁺=639.

Preparation of I-42 Example 42

6-tert-Butyl-8-fluoro-2-[2-hydroxymethyl-3-(5-{5-[(2-methoxy-ethylamino)-methyl]-pyridin-2-ylamino}-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl)-phenyl]-2H-phthalazin-1-onewas prepared using the general procedure described in Example 41,substituting 2-methoxyethanamine for 1-methylpiperazine in step 1. Thesecondary amine was protected with a BOC group using a standardprocedure prior to the second step of the synthesis. In the penultimatestep of the synthesis for this compound, 1M NaOH was used to remove theacetate protecting group rather than potassium carbonate, using THF asthe solvent and heating at 60° C. for two hours, then stirring at roomtemperature overnight. The BOC protecting group was removed at the endof the synthesis by heating the compound in1,1,1,3,3,3-hexafluoro-2-propanol (used in large excess as the solvent)in a microwave at 140° C. for 30 minutes. After purification bychromatography using a gradient of 5% to 25% methanol in DCM, 75 mg ofproduct was obtained as a yellow solid. ¹H NMR (300 MHz, DMSO-d6) δ ppm9.37 (s, 1H) 8.51-8.54 (m, 2H) 8.20 (d, J=2.3 Hz, 1H) 7.87 (s, 1H) 7.75(d, J=14.4 Hz, 1H) 7.64-7.69 (m, 1H) 7.42-7.59 (m, 4H) 4.57 (t, J=5.3Hz, 1H) 4.42 (br. s., 2H) 3.77 (s, 3H) 3.61 (s, 2H) 3.37 (t, J=5.7 Hz,2H) 3.21 (s, 3H) 2.55-2.64 (m, 2H) 1.37 (s, 9H). MS: (M+H)⁺=614.MP=108-110° C.

Preparation of I-43

(1S,4S)-5-(6-Chloro-pyridin-3-ylmethyl)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylicacid tert-butyl ester was prepared as described in example 41 (step 1)except substituting (1S,4S)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylicacid tert-butyl ester for 1-methylpiperazine.

Preparation of(1S,4S)-2-(6-Chloro-pyridin-3-ylmethyl)-5-methyl-2,5-diazabicyclo[2.2.1]-heptane:(1S,4S)-5-(6-Chloro-pyridin-3-ylmethyl)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylicacid tert-butyl ester (1.1 g, 3.4 mmol) was dissolved in a mixture of11.3 ml of formic acid and 22.6 ml of formalin. The reaction was heatedat 70° C. for 4 hours, and then cooled to room temperature. Water wasadded and the aqueous layer was extracted with DCM. The aqueous layerwas carefully basified with solid potassium carbonate and extracted 3times with DCM. The crude product was purified by chromatography using agradient of 5% to 25% methanol in DCM. Ammonium hydroxide (approximately2%) had been added to the methanol. 500 mg of a colorless liquid wasobtained (61.9%).

Example 43

Preparation of6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-((1S,4S)-5-methyl-2,5-diaza-bicyclo[2.2.1]hept-2-ylmethyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one:6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-((1S,4S)-5-methyl-2,5-diaza-bicyclo[2.2.1]hept-2-ylmethyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-onewas prepared using the general procedure described in example 41substituting(1S,4S)-2-(6-Chloro-pyridin-3-ylmethyl)-5-methyl-2,5-diazabicyclo[2.2.1]-heptanefor 1-((6-chloropyridin-3-ylmethyl)-4-methylpiperazine in step 2 andusing NaOH in THF to remove the acetate protecting group rather thanpotassium carbonate. 46 mg (98%) of an off-white powder was obtained. ¹HNMR (300 MHz, DMSO-d6) δ ppm 9.38 (s, 1H) 8.54 (s, 1H) 8.52 (d, J=2.3Hz, 1H) 8.20 (d, J=1.9 Hz, 1H) 7.87 (s, 1H) 7.72-7.76 (m, 1H) 7.64 (dd,J=8.5, 2.1 Hz, 1H) 7.43-7.59 (m, 4H) 4.58 (t, J=6.0 Hz, 1H) 4.41 (br.s., 2H) 3.79 (s, 3H) 3.49-3.61 (m, 2H) 3.18 (s, 1H) 3.09 (s, 1H)3.49-3.61 (m, 2H) 2.54-2.66 (m, 2H) 2.24 (s, 3H) 1.57 (s, 2H) 1.38 (s,9H). MS: (M+H)⁺=651. MP=183-186° C.

Preparation of I-44

6-Chloro-4-(5-{[(2-methoxy-ethyl)-methyl-amino]-methyl}-pyridin-2-ylamino)-2-methyl-2H-pyridazin-3-onewas prepared using the general procedure described in Example 41 (step1-2), substituting 2-methoxyethanamine for 1-methylpiperazine in step 1.The secondary amine was protected with a BOC group using a standardprocedure.

Preparation of6-Chloro-4-(5-{[(2-methoxy-ethyl)-methyl-amino]-methyl}-pyridin-2-ylamino)-2-methyl-2H-pyridazin-3-one:tert-Butyl(6-(6-chloro-2-methyl-3-oxo-2,3-dihydropyridazin-4-ylamino)pyridin-3-yl)methyl(2-methoxyethyl)carbamate(95 mg, 0.22 mmol) was dissolved in 0.75 ml of formic acid and 1.4 ml offormalin. The reaction was heated at 70° C. for 4 hours. The reactionwas cooled to room temperature, water was added and the aqueous layerwas extracted with DCM. The aqueous layer was carefully basified withsolid potassium carbonate and extracted 3 times with DCM. The crudeproduct was purified by chromatography using a gradient of 5% to 15%methanol in DCM to give 50 mg (66.0%) of a white powder.

Example 44

Preparation of6-tert-Butyl-8-fluoro-2-{2-hydroxymethyl-3-[5-(5-{[(2-methoxy-ethyl)-methyl-amino]-methyl}-pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl]-phenyl}-2H-phthalazin-1-one:6-tert-Butyl-8-fluoro-2-{2-hydroxymethyl-3-[5-(5-{[(2-methoxy-ethyl)-methyl-amino]-methyl}-pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl]-phenyl}-2H-phthalazin-1-onewas prepared using the general procedure described in example 41substituting6-Chloro-4-(5-{[(2-methoxy-ethyl)-methyl-amino]-methyl}-pyridin-2-ylamino)-2-methyl-2H-pyridazin-3-onefor6-chloro-2-methyl-4-(5-((4-methylpiperazin-1-yl)methyl)pyridin-2-ylamino)pyridazin-3(2H)-onein step 3. For the Suzuki reaction, potassium(2-(acetoxymethyl)-3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)phenyl)trifluoroborate(Eq: 1.2) was used in place of2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate. After removal of the acetate protecting group using potassiumcarbonate in methanol, water was added dropwise and the reaction wasstirred at room temperature overnight. The solid that formed wasfiltered, washed with water then ether and dried in a vacuum oven togive 52 mgs of a crystalline white solid. ¹H NMR (300 MHz, DMSO-d₆) δppm 1.38 (s, 9H) 2.13 (s, 3H) 2.47 (s, 2H) 3.22 (s, 3H) 3.39-3.49 (m,4H) 3.79 (s, 3H) 4.43 (br. s., 2H) 4.58 (br. s., 1H) 7.41-7.65 (m, 5H)7.75 (d, J=13.22 Hz, 1H) 7.87 (s, 1H) 8.17 (s, 1H) 8.46-8.59 (m, 2H)9.40 (s, 1H). MS: (M+H)⁺=628.

Preparation of I-45 Example 45

6-(4-Methyl-piperazin-1-yl)-pyridazin-3-ylamine:6-Chloro-pyridazin-3-ylamine (2.0 g, 15.4 mmol, Eq: 1.00) was dissolvedin 1-methylpiperazine (15.5 g, 154 mmol, Eq: 10.0) and heated in a sandbath at 165° C. for 4 hours. The reaction mixture was then heated at200° C. for 2 hours in a microwave reactor. The crude product waspurified by chromatography using 10% methanol (with approximately 2%ammonium hydroxide) in DCM. To the still impure product was addedaqueous sodium bicarbonate and DCM and the layers were separated. Theaqueous layer was back extracted twice with DCM. The combined organiclayers were concentrated, triturated with isopropyl acetate, filteredand dried to give 730 mg (24.5%) of a yellow solid.

6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[6-(4-methyl-piperazin-1-yl)-pyridazin-3-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one:6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[6-(4-methyl-piperazin-1-yl)-pyridazin-3-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-onewas prepared using the general procedure described in Example 41,substituting potassium(2-(acetoxymethyl)-3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)phenyl)trifluoroborate(Eq: 1.2) for2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate. After removal of the acetate protecting group with potassiumcarbonate in methanol, the product was purified by preparative TLC using20% methanol in DCM to give 30 mgs of final product. ¹H NMR (300 MHz,DMSO-d₆) δ ppm 1.38 (s, 9H) 2.21 (s, 3H) 2.34-2.44 (m, 4H) 3.44-3.53 (m,4H) 3.79 (s, 3H) 4.41 (br. s., 1H) 4.50-4.61 (m, 1H) 7.39 (d, J=9.82 Hz,1H) 7.44-7.60 (m, 3H) 7.66 (d, J=9.82 Hz, 1H) 7.75 (d, J=13.22 Hz, 1H)7.87 (s, 1H) 8.45 (s, 1H) 8.51 (d, J=2.27 Hz, 1H) 9.38 (s, 1H). MS:(M+H)⁺=626.

Preparation of I-46

Step 1

(1 S,4S)-tert-Butyl5-methyl-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate:(1S,4S)-tert-Butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (2.5 g,12.6 mmol, Eq: 1.00) was dissolved in 126 ml of methanol. Formaldehyde(23.5 ml of a 37% aqueous solution) and acetic acid (2.17 ml) wereadded. Sodium triacetoxyborohydride (4.01 g, 18.9 mmol, Eq: 1.50) wasadded in portions. The reaction was stirred at room temperatureovernight. The reaction was concentrated on a rotary evaporator. DCM andsodium bicarbonate were added to the residue and the layers wereseparated. The organic layer was washed with dilute bicarbonate,concentrated, and used without further purification.

Step 2

(1S,4S)-2-methyl-2,5-diazabicyclo[2.2.1]heptane: (1S,4S)-tert-Butyl5-methyl-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (2.5 g, 11.8 mmol)was dissolved a 50% mixture of DCM and TFA. The reaction was stirred atroom temperature for 1 hour. The solvents were evaporated. DCM andaqueous sodium hydroxide were added to the residue and the layers wereseparated. The aqueous layer was back extracted two more times with DCM.The combined organic layers were concentrated and the crude product wasused without purification.

Step 3

6-((1S,4S)-5-Methyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-pyridazin-3-ylamine:6-Chloropyridazin-3-amine (200 mg, 1.54 mmol, Eq: 1.00) and(1S,4S)-2-methyl-2,5-diazabicyclo[2.2.1]heptane (693 mg, 6.18 mmol, Eq:4.00) were combined in a small round bottom flask and heated at 200° C.for 2 hours. The dark glassy residue was dissolved in DCM and purifiedby chromatography using a gradient of 0% to 25% methanol (with 2.5%ammonium hydroxide) in DCM to give about 100 mg (31.6%) of a brown,viscous oil.

Step 4

Acetic acid2-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-6-{1-methyl-5-[6-((1S,4S)-5-methyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-pyridazin-3-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-benzylester:6-((1S,4S)-5-Methyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-pyridazin-3-ylamine(100 mg, 0.487 mmol, Eq: 1.00), acetic acid2-(5-bromo-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl)-6-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-benzylester (284 mg, 0.512 mmol, Eq: 1.05), xantphos (42.3 mg, 0.073 mmol, Eq:0.15), tris(dibenzylideneacetone)-dipalladium (0) (33.5 mg, 0.036 mmol,Eq: 0.075) and cesium carbonate (476 mg, 1.46 mmol, Eq: 3.00) were addedto a microwave vial. The vial was capped and purged. Degassed dioxane(about 5 ml) was added through a syringe and the vial was purged againand back filled with nitrogen. The reaction was heated at 100° C.overnight in a sand bath. The reaction was filtered through celite andconcentrated. The crude product was purified by chromatography using agradient of 0% to 25% methanol in DCM. LCMS and NMR showed majorimpurities. Took on to next step without further purification.

Example 46 Step 5

6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[6-((1S,4S)-5-methyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-pyridazin-3-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one:The impure mixture from the prior reaction was dissolved in methanol,potassium carbonate was added, and the reaction was heated at 40° C. for1 hour. Water was added and the reaction was stirred at room temperatureovernight. The solid that formed was filtered and dried. The crudeproduct was purified by preparative TLC in 10% methanol in DCM. Theplates were eluted twice to give 5 mg of a light yellow solid which wasapproximately 85% pure. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.40 (s, 9H)1.70-1.79 (m, 1H) 1.83-1.92 (m, 1 H) 2.26 (s, 3H) 2.42 (d, J=9.06 Hz,1H) 2.70-2.85 (m, 1H) 3.37-3.55 (m, 4H) 3.79 (s, 3H) 4.33-4.66 (m, 3H)7.06 (d, J=9.82 Hz, 1H) 7.44-7.57 (m, 3H) 7.64 (d, J=9.44 Hz, 1H) 7.75(dd, J=13.41, 1.70 Hz, 1H) 7.88 (d, J=1.89 Hz, 1H) 8.42 (s, 1H) 8.52 (d,J=2.64 Hz, 1H) 9.32 (s, 1H). MS: (M+H)⁺=638.

Preparation of I-47 Example 47

Step 1. Preparation of6-(6-Chloro-2-methyl-3-oxo-2,3-dihydro-pyridazin-4-ylamino)-nicotinicacid methylester

Methy 6-aminonicotinate (2 g, 13.1 mmol, Eq: 1.00),4-bromo-6-chloro-2-methylpyridazin-3(2H)-one (2.94 g, 13.1 mmol, Eq: 1),and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis-(diphenylphosphine) (400 mg,691 μmol, Eq: 0.0526) were dissolved in DMF (300 ml) under heating.Cesium carbonate (12.8 g, 39.4 mmol, Eq: 3) was added followed byPd₂(dba)₃ (301 mg, 329 μmol, Eq: 0.025) under an argon atmosphere. Thereaction mixture was heated to 105° C. over night. The crude reactionmixture was poured into water (400 ml) and the resulting precipitate wasfiltered off and washed with water. The resultant filter cake wasdissolved in dichloromethane. The organic phase was washed with brine,dried over sodium sulfate; filtered and concentrated to give the desiredproduct as an off-white solid (1.523 g).

(M+H)⁺=294.9 m/e

Step 2. Preparation of6-(6-Chloro-2-methyl-3-oxo-2,3-dihydro-pyridazin-4-ylamino)-nicotinicacid

Methyl6-(6-chloro-2-methyl-3-oxo-2,3-dihydropyridazin-4-ylamino)nicotinate(1.523 g, 5.17 mmol, Eq: 1.00) was suspended in dioxane (90 ml). 1 MLithium hydroxide (10.3 ml, 10.3 mmol, Eq: 2) was added dropwise. Thelight brown suspension was stirred overnight at room temperature. 1 MLithium hydroxide (10.3 ml, 10.3 mmol, Eq: 2) was added again andstirred over the weekend. A mixture of ethyl acetate/ammonium chloridesolution was added to the reaction mixture. The resulting precipitatewas collected by filtration. The precipitate was triturated with water(200 ml), filtered, washed with ethyl acetate and dried in vacuo to givea light yellow solid (1.13 g). (M+H)⁺=278.8 m/e

Step 3.4-[5-(azetidine-1-carbonyl)-pyridin-2-ylamino]-6-chloro-2-methyl-2H-pyridazin-3-one

6-(6-chloro-2-methyl-3-oxo-2,3-dihydropyridazin-4-ylamino)nicotinic acid(100 mg, 356 μmol, Eq: 1.00) was suspended in dichloromethane. Oxalylchloride (67.8 mg, 46.8 μl, 534 μmol, Eq: 1.5) was added followed by adrop of DMF (10 μl) and the reaction mixture was stirred for 2 hr atroom temperature. The reaction mixture was concentrated. The acidchloride was used as is for the next step. It was dissolved indichloromethane (10 ml). To that was added azetidine (20.3 mg, 24.0 μl,356 μmol, Eq: 1.00) followed by DIEA (230 mg, 311 μl, 1.78 mmol, Eq: 5)and the reaction was stirred over night at room temperature. Thereaction mixture was diluted with dichloromethane, washed with asaturated sodium carbonate solution, washed with brine, dried oversodium sulfate, filtered and concentrated to give a light brown solid(145 mg) which was triturated with DCM/Hex/EtOAc to give the desiredproduct as a yellow solid (56 mg).

(M+H)⁺=320.0 m/e

Step 4. Preparation of2-(3-{5-[5-(Azetidine-1-carbonyl)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-2-hydroxymethyl-phenyl)-6-tert-butyl-8-fluoro-2H-phthalazin-1-one

4-(5-(azetidine-1-carbonyl)pyridin-2-ylamino)-6-chloro-2-methylpyridazin-3(2H)-one(56 mg, 175 μmol, Eq: 1.00), potassium(2-(acetoxymethyl)-3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)phenyl)trifluoroborate(83.1 mg, 175 μmol, Eq: 1), x-phos (13.0 mg, 27.3 μmol, Eq: 0.156) andpotassium phosphate tribasic (81.8 mg, 385 μmol, Eq: 2.2) were dissolvedin a 10% aq. methanol solution (10 ml). The reaction was degassed.Finally bis(dibenzylideneacetone)palladium (9.06 mg, 15.8 μmol, Eq:0.09) was added and the reaction mixture was stirred at 100° C. for 100min. The reaction mixture was filtered and the filtercake was washedwith methanol. The combined filtrate and washes were concentrated andextracted with ethyl acetate and water. The organic phase was separated,washed with brine, dried over sodium sulfate, filtered and concentrated.The residue was dissolved in ethyl acetate. Hexane was added untilprecipitate was formed. The precipitate was filtered off to give crudeproduct as a yellow solid. This crude product was purified by silica gelchromatography to give a yellow solid which was dissolved in dioxane. 1M sodium hydroxide solution (263 μl, 263 μmol, Eq: 1.5) was added andthe resulting reaction mixture was stirred over night at roomtemperature. The reaction mixture was treated again with 1 M sodiumhydroxide solution (10 eq.) and heated to 40° C. for 4 hr. The reactionwas diluted with dichlormethane and water and extracted withdichloromethane to give a crude solid after concentration. The crudeproduct was purified by 12 g silica gel chromatography eluting with0-10% methanol in ethyl acetate to afford2-(3-{5-[5-(Azetidine-1-carbonyl)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-2-hydroxymethyl-phenyl)-6-tert-butyl-8-fluoro-2H-phthalazin-1-oneas a light yellow solid (16 mg).

(M+H)⁺=610.1 m/e

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.42 (s, 9H) 2.38 (quin, J=7.70 Hz,2H) 3.79 (br. s, 1H) 3.91 (s, 3H) 4.25 (br. s., 2H) 4.43 (br. s., 4H)6.99 (d, J=8.69 Hz, 1H) 7.44-7.70 (m, 5H) 8.00 (dd, J=8.69, 2.27 Hz, 1H)8.29 (d, J=2.64 Hz, 1H) 8.47 (s, 1H) 8.60 (d, J=2.27 Hz, 1H) 8.71 (s,1H).

Preparation of I-48 Example 48

Preparation by a similar procedure to Example 47, except substitutingthiomorpholine 1,1-dioxide for azetidine in step 3, afforded6-tert-Butyl-2-(3-{5-[5-(1,1-dioxo-1λ⁶-thiomorpholine-4-carbonyl)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-2-hydroxymethyl-phenyl)-8-fluoro-2H-phthalazin-1-one(M+H)⁺=687.9 m/e

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.43 (s, 9H) 3.12 (br. s., 4H) 3.76(br. s, 1H) 3.91 (s, 3H) 4.13 (br. s., 4H) 4.44 (s, 2H) 7.04 (d, J=8.31Hz, 1H) 7.44-7.67 (m, 5H) 7.78 (dd, J=8.69, 2.27 Hz, 1H) 8.29 (d, J=2.64Hz, 1H) 8.46 (d, J=2.27 Hz, 1H) 8.54 (s, 1H) 8.71 (s, 1H)

Preparation of I-49 Example 49

Preparation by a similar procedure to Example 47, except substituting2-oxa-6-aza-spiro[3.3]heptane for azetidine in step 3, afforded2-(3-(5-(5-(2-oxa-6-azaspiro[3.3]heptane-6-carbonyl)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-(hydroxymethyl)phenyl)-6-tert-butyl-8-fluorophthalazin-1(2H)-one

(M+H)⁺=652.1 m/e

¹H NMR (300 MHz, CHLOROFORM-d) δ: ppm 1.43 (s, 9H) 3.92 (s, 3H)4.29-4.61 (m, 6H) 4.83 (s, 4H) 7.00 (d, J=8.69 Hz, 1H) 7.45-7.68 (m, 5H)7.98 (dd, J=8.69, 2.27 Hz, 1H) 8.29 (d, J=2.64 Hz, 1H) 8.50 (s, 1H) 8.58(d, J=2.27 Hz, 1H) 8.72 (s, 1H)

Preparation of I-50 Example 50

Preparation by a similar procedure to Example 1, except substituting2-methyl-2,6-diaza-spiro[3.3]heptane for azetidine in step 3, afforded6-tert-butyl-8-fluoro-2-(2-(hydroxymethyl)-3-(1-methyl-5-(5-(6-methyl-2,6-diazaspiro[3.3]heptane-2-carbonyl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)phthalazin-1(2H)-one

(M+H)⁺=665.1 m/e

¹H NMR (300 MHz, CHLOROFORM-d) δ: ppm 1.38-1.47 (m, 9H) 2.38 (s, 3H)3.52 (br. s., 4 H) 3.91 (s, 3H) 4.26 (br. s., 2H) 4.44 (s, 4H) 6.96 (d,J=8.69 Hz, 1H) 7.41-7.78 (m, 5H) 7.95 (dd, J=8.50, 2.08 Hz, 1H) 8.30 (d,J=2.27 Hz, 1H) 8.48 (s, 1H) 8.57 (d, J=1.89 Hz, 1H) 8.68-8.71 (m, 1H)

Preparation of I-51 Example 51

Preparation by a similar procedure to Example 47, except substitutingN,N-dimethyl-ethane-1,2-diamine for azetidine in step 3, afforded6-(6-(3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-2-(hydroxymethyl)phenyl)-2-methyl-3-oxo-2,3-dihydropyridazin-4-ylamino)-N-(2-(dimethylamino)ethyl)nicotinamide

(M+H)⁺=641.1 m/e

¹H NMR (300 MHz, CHLOROFORM-d) δ: ppm 1.41 (s, 9H) 2.35 (s, 6H) 2.62(br. t, J=1.00, 1.00 Hz, 2H) 3.56 (t, J=4.90 Hz, 2H) 3.84 (m, J=7.20 Hz,1H) 3.92 (s, 3H) 4.44 (br. s., 2H) 6.98 (d, J=8.69 Hz, 1H) 7.46-7.71 (m,5H) 8.14 (d, J=9.44 Hz, 1H) 8.29 (s, 1H) 8.46 (s, 1H) 8.72-8.82 (m, 2H)

Preparation of I-52 Example 52

Preparation by a similar procedure to Example 47, except substituting2-methylamino-ethanol for azetidine in step 3, afforded6-(6-(3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-2-(hydroxymethyl)phenyl)-2-methyl-3-oxo-2,3-dihydropyridazin-4-ylamino)-N-(2-hydroxyethyl)-N-methylnicotinamide

(M+H)⁺=628.1 m/e

¹H NMR (300 MHz, CHLOROFORM-d) δ: ppm 1.39-1.47 (m, 9H) 3.15 (s, 3H)3.59-3.90 (m, 4H) 3.91 (s, 3H) 4.43 (d, J=5.67 Hz, 2H) 6.99 (d, J=8.31Hz, 1H) 7.45-7.69 (m, 5H) 7.81 (dd, J=8.69, 2.27 Hz, 1H) 8.29 (d, J=2.64Hz, 1H) 8.46 (s, 1H) 8.50 (d, J=2.27 Hz, 1H) 8.70 (s, 1H)

Preparation of I-53 Example 53

Preparation by a similar procedure to Example 47, except substitutingazetidine-3-carbonitrile for azetidine in step 3, afforded1-(6-(6-(3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-2-(hydroxymethyl)phenyl)-2-methyl-3-oxo-2,3-dihydropyridazin-4-ylamino)nicotinoyl)azetidine-3-carbonitrile

MS (m−1)=633.2

¹H NMR (300 MHz, CHLOROFORM-d) δ: ppm 1.44 (s, 9H) 3.54-3.68 (m, 2H)3.93 (s, 3H) 4.44 (s, 2H) 4.49-4.71 (m, 2H) 7.01 (d, J=8.69 Hz, 1H)7.45-7.70 (m, 5H) 7.98 (dd, J=1.00 Hz, 1H) 8.30 (d, J=2.27 Hz, 1H) 8.50(s, 1H) 8.56 (s, 1H) 8.73 (s, 1H)

Preparation of I-54 Example 54

Preparation by a similar procedure to Example 47, except substitutingpyrrolidin-3-ol for azetidine in step 3, afforded6-tert-butyl-8-fluoro-2-(2-(hydroxymethyl)-3-(5-(5-(3-hydroxypyrrolidine-1-carbonyl)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)phthalazin-1(2H)-one

(M−H)=640.1 m/e

¹H NMR (300 MHz, CHLOROFORM-d) δ: ppm 1.41 (s, 9H) 1.99 (br. s., 2H)3.38-4.00 (m, 9 H) 4.42 (br. s., 2H) 4.48-4.60 (m, 1H) 6.93-7.07 (m, 1H)7.39-7.72 (m, 5H) 7.80-7.89 (m, 1H) 8.29 (d, J=2.27 Hz, 1H) 8.43-8.61(m, 2H) 8.70 (s, 1H)

Preparation of I-55 Example 55

Preparation by a similar procedure to Example 47, except substituting1-methylamino-pentan-3-ol for azetidine in step 3, afforded6-tert-butyl-8-fluoro-2-(2-(hydroxymethyl)-3-(5-(5-(4-hydroxypiperidine-1-carbonyl)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)phthalazin-1(2H)-one.(M+H)⁺=654.0 m/e. ¹H NMR (300 MHz, CHLOROFORM-d) δ: ppm 1.42 (s, 9H)1.58 (br. s., 3H) 1.87-2.02 (m, 2H) 3.29-3.45 (m, 2H) 3.65 (s, 1H) 3.81(t, J=1.00 Hz, 1H) 3.93 (s, 3H) 3.97-4.07 (m, 2H) 4.43 (d, J=6.42 Hz,2H) 6.99 (d, J=8.31 Hz, 1H) 7.45-7.69 (m, 5H) 7.76 (dd, J=8.31, 2.27 Hz,1H) 8.29 (d, J=2.64 Hz, 1H) 8.41-8.45 (m, 2H) 8.69 (s, 1H)

Preparation of I-56

Example 566-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methyl-piperazin-1-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one

To a solution of 1-methyl-4-(6-nitropyridin-3-yl)piperazine (500 mg,2.25 mmol) in ethanol (20 mL) was added 10% Pd/C (80 mg, 0.75 mmol) andthe resulting mixture was stirred under a hydrogen atmosphere for 18 h.The reaction mixture was filtered through celite, washed with ethanoland concentrated to give 5-(4-methylpiperazin-1-yl)pyridin-2-amine.

A solution of 5-(4-methylpiperazin-1-yl)pyridin-2-amine (172 mg, 0.90mmol), 4-bromo-6-chloro-2-methylpyridazin-3(2H)-one (200 mg, 0.90 mmol)cesium carbonate (1.02 g, 3.13 mmol) and4,5-bis(diphenylphosphino)-9,9-dimethlxanthene (77.7 mg, 0.13 mmol) indioxane (10 ml) was flushed with argon beforetris(dibenzylideneacetone)dipalladium(0) (61.5 mg, 0.07 mmol) was addedand the resulting solution was heated at 90° C. for 18 h. The mixturewas cooled to room temperature and diluted with dichloromethane andwater. The layers were separated and the aqueous layer was extractedwith dichloromethane (2×25 mL). The organic layers were combined, driedover magnesium sulfate. The resulting mixture was filtered andconcentrated in vacuo. The residue was triturated with methanol anddichloromethane and filtered, washed with ether and dried to give6-chloro-4-[5-(4-methyl-piperazin-1-yl)-pyridin-2-ylamino]-2-methyl-2H-pyridazin-3-one(223 mg, 74%) as a yellow solid.

A solution of2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate (221 mg, 0.45 mmol),6-chloro-4-(5-(4-methylpiperazin-1-yl)pyridin-2-ylamino)-2-methylpyridazin-3(2H)-one(100 mg, 0.30 mmol), potassium phosphate (159 mg, 0.75 mmol) anddicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (14.2 mg, 0.03mmol) in butanol (4 ml) and water (1 mL) was flushed with argon before(bis[dibenzylideneacetone] dipalladium) (8.59 mg, 0.01 mmol) was addedand the resulting solution heated at 100° C. in for 2 h. The resultingmixture was cooled, poured into a saturated solution of ammoniumchloride and extracted with methylene chloride (2×100 mL). The layerswere separated and the organic phase dried over magnesium sulfate. Themixture was filtered and concentrated in vacuo. The residue wasdissolved in dioxane (10 mL) and treated with a lithium hydroxidesolution (0.5 mL, 2.0 M), and the resulting mixture was stirred at roomtemperature overnight. The resulting mixture was poured into a saturatedammonium chloride solution and extracted with methylene chloride (2×50mL). The layers were separated and the organic phase dried overmagnesium sulfate. The mixture was filtered and concentrated in vacuo.The residue was purified by flash chromatography (silica gel, 24 g, 1%to 14% methanol in dichloromethane) and recrystallized fromdichloromethane and isopropyl acetate to give6-tert-butyl-2-(3-{5-[5-(4-methyl-piperazin-1-yl)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-2-hydroxymethyl-phenyl)-8-fluoro-2H-phthalazin-1-one(45 mg, 24%) as a light yellow solid: mp 260-264° C.; ¹H NMR (300 MHz,DMSO-d₆) δ: ppm 1.38 (s, 9H) 2.20 (s, 3H) 2.33-2.46 (m, 4H) 2.98-3.19(m, 4H) 3.77 (s, 3H) 4.27-4.69 (m, 3H) 7.24-8.07 (m, 8H) 8.32-8.74 (m,2H) 9.23 (s, 1H).

Preparation of I-57

Example 576-tert-Butyl-2-(3-{5-[5-((S)-1,2-dihydroxy-ethyl)-pyrazin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-2-hydroxymethyl-phenyl)-8-fluoro-2H-phthalazin-1-one

A solution of (S)-5-(2,2-dimethyl-1,3-dioxolan-4-yl)pyrazin-2-amine(prepared as in WO2004052869, Example 54, 175 mg, 0.90 mmol),4-bromo-6-chloro-2-methylpyridazin-3(2H)-one (200 mg, 0.90 mmol), cesiumcarbonate (1.02 g, 3.13 mmol) and4,5-bis(diphenylphosphino)-9,9-dimethlxanthene (77.7 mg, 0.13 mmol) indioxane (10 ml) was flushed with argon beforetris(dibenzylideneacetone)dipalladium(0) (61.5 mg, 0.07 mmol) was addedand the resulting solution was heated at 90° C. for 18 h. The mixturewas cooled to room temperature and diluted with dichloromethane (50 mL)and water. The layers were separated and the aqueous layer was extractedwith dichloromethane (2×25 mL). The organic layers were combined, driedover magnesium sulfate. The resulting mixture was filtered andconcentrated in vacuo. The precipitate formed was isolated byfiltration, washed with ether and dried under vacuum to give6-chloro-4-[5-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-pyrazin-2-ylamino]-2-methyl-2H-pyridazin-3-one(150 mg, 50%) as a yellow solid.

A solution of2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate (307 mg, 0.62 mmol),(S)-6-chloro-4-(5-(2,2-dimethyl-1,3-dioxolan-4-yl)pyrazin-2-ylamino)-2-methylpyridazin-3(2H)-one(150 mg, 0.44 mmol), potassium phosphate (236 mg, 0.01 mmol) anddicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (21.2 mg, 0.04mmol) in butanol (4 ml) and water (1 mL) was flushed with argon before(bis[dibenzylideneacetone] dipalladium) (12.8 mg, 0.02 mmol) was addedand the resulting solution heated at 100° C. in for 2 h. The resultingmixture was cooled, poured into a saturated solution of ammoniumchloride and extracted with methylene chloride (2×100 mL). The layerswere separated and the organic phase dried over magnesium sulfate. Themixture was filtered and concentrated in vacuo. The residue wasdissolved in dioxane (10 mL) and treated with a lithium hydroxidesolution (0.5 mL, 2.0 M), and the resulting mixture was stirred at roomtemperature overnight. The resulting mixture was poured into a saturatedammonium chloride solution and extracted with methylene chloride (2×150mL). The layers were separated and the organic phase dried overmagnesium sulfate. The mixture was filtered and concentrated in vacuo.The residue was purified by flash chromatography (silica gel, 24 g, 1%to 7% methanol in dichloromethane) to give(S)-6-tert-butyl-2-(3-(5-(5-(2,2-dimethyl-1,3-dioxolan-4-yl)pyrazin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-(hydroxymethyl)phenyl)-8-fluorophthalazin-1(2H)-one(99 mg, 36%) as a light yellow solid.

To a solution of(S)-6-tert-butyl-2-(3-(5-(5-(2,2-dimethyl-1,3-dioxolan-4-yl)pyrazin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-(hydroxymethyl)phenyl)-8-fluorophthalazin-1(2H)-one(99 mg, 0.16 mmol) in tetrahydrofuran (4 mL) was added hydrochloric acid(1.0 N, 4 mL) and the resulting mixture stirred at room temperatureovernight. The reaction mixture was poured into a saturated ammoniumchloride solution and extracted with dichloromethane (2×50 mL). Thecombined organic layers were dried over magnesium sulfate. The mixturewas filtered and evaporated and the residue recrystallized fromdichloromethane and isopropyl acetate to give6-tert-butyl-2-(3-{5-[5-((S)-1,2-dihydroxy-ethyl)-pyrazin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-2-hydroxymethyl-phenyl)-8-fluoro-2H-phthalazin-1-one(15.4 mg, 17%) as an off white solid: Mp. 218-224° C.; ¹H NMR (300 MHz,DMSO-d₆) δ ppm 1.37 (s, 10H) 3.44-3.95 (m, 5H) 4.32-4.82 (m, 4H) 5.40(d, J=4.91 Hz, 1H) 7.22-7.99 (m, 5H) 8.16-8.65 (m, 3H) 8.78 (s, 1H) 9.81(s, 1H).

Preparation of I-58

Example 58 Acetic acid2-[5-(5-azetidin-1-ylmethyl-1-methyl-1H-pyrazol-3-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl]-6-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-benzylester

To a solution of 5-nitro-1H-pyrazole-3-carboxylic acid (1.13 g, 7.19mmol) in anhydrous methanol (20 ml) at to 0° C. was added thionylchloride (2.23 g, 1.37 ml, 18.7 mmol) dropwise. The resulting solutionwas heated to reflux for 2 h. The cooled solution was evaporated todryness to give 5-nitro-2H-pyrazole-3-carboxylic acid methyl ester (1.17g, 95%) as a white solid.

To a solution of methyl 5-nitro-1H-pyrazole-3-carboxylate (1.87 g, 10.9mmol) in anhydrous dimethyl formamide (20 mL) was added potassiumcarbonate (3.02 g, 21.9 mmol) and methyl iodide (2.02 g, 0.89 mL, 14.2mmol) and the resulting solution stirred at room temperature for 18 h.The resulting mixture was diluted with water (1×150 mL) and extractedwith dichloromethane (3×75 mL). The combined organic layers were driedover magnesium sulfate. The mixture was filtered and evaporated and theresidue purified by flash chromatography (silica gel, 25 g, 20% to 60%dichloromethane in hexanes) to give a mixture of2-methyl-5-nitro-2H-pyrazole-3-carboxylic acid methyl ester and1-methyl-5-nitro-1H-pyrazole-3-carboxylic acid methyl ester (1.64 g,81%) as a white solid.

To a solution of 2-methyl-5-nitro-2H-pyrazole-3-carboxylic acid methylester and 1-methyl-5-nitro-1H-pyrazole-3-carboxylic acid methyl ester(1.18 g, 6.37 mmol) in tetrahydrofuran (20 mL) at 0° C. was added alithium aluminum hydride solution (1.0M in tetrahydrofuran, 7.65 mL,7.65 mmol) drop wise. The resulting mixture was stirred at 0° C. for 20min. To this solution was added ethyl acetate (1 mL) followed by fewcrystals of sodium sulphate decahydrate. The resulting mixture wasstirred for 30 min then filtered, the filter cake washed with ethylacetate and the filtrate evaporated. The residue was purified by flashchromatography (silica gel, 80 g, 50% to 70% ethyl acetate in hexanes)to give 1-methyl-3-nitro-1H-pyrazol-5-yl)methanol (496 mg, 50%) as awhite solid.

To a solution of (1-methyl-3-nitro-1H-pyrazol-5-yl)methanol (496 mg,3.16 mmol) in chloroform (10 mL) at 0° C. was added phosphorustribromide (854 mg, 0.30 mL, 3.16 mmol) drop wise via syringe. Theresulting solution was warmed to room temperature and stirred for 1 h.The resulting solution was cooled to 0° C. and diluted withdichloromethane (50 ml). The resulting solution was made basic (pH 8.5)with saturated aqueous sodium bicarbonate (20 mL). The layers wereseparated, and the aqueous layer was extracted with dichloromethane(3×20 mL). The combined organic layers were dried over magnesiumsulfate. The resulting mixture was filtered and concentrated in vacuoand the residue purified by flash chromatography (silica gel, 40 g, 20%to 40% ethyl acetate in hexanes) to give5-(bromomethyl)-1-methyl-3-nitro-1H-pyrazole (436 mg, 63%) as a whitesolid.

To a solution of 5-(bromomethyl)-1-methyl-3-nitro-1H-pyrazole (436 mg,1.98 mmol) in tetrahydrofuran (10 mL) was added azetidine (141 mg, 0.17mL, 2.48 mmol) and diisopropylethyl amine (307 mg, 0.42 mL, 2.38 mmol)drop wise and the resulting mixture was stirred at room temperature for24 h. The solution was concentrated and the residue dissolved indichloromethane (50 mL), washed with water (50 mL). The aqueous layerwas extracted with methylene chloride (2×50 mL) and the organic phasescombined and dried over magnesium sulfate. The resulting mixture wasfiltered and evaporated and the residue purified by flash chromatography(40 g, 1% to 5% methanol in dichloromethane) to give5-(azetidin-1-ylmethyl)-1-methyl-3-nitro-1H-pyrazole (349 mg, 90%) as acolorless oil.

To a solution of 5-(azetidin-1-ylmethyl)-1-methyl-3-nitro-1H-pyrazole(349 mg, 1.78 mmol) in ethanol (20 mL) was treated with palladium oncarbon (10%, 50 mg). The resulting mixture was stirred under a hydrogen(1 atm) for 48 h. The reaction mixture was filtered through a celitepad, and the pad washed with ethanol. The filtrate was concentrated invacuo to give 5-(azetidin-1-ylmethyl)-1-methyl-1H-pyrazol-3-amine (292mg, 99%) as a light yellow oil.

A solution of 5-(azetidin-1-ylmethyl)-1-methyl-1H-pyrazol-3-amine (292mg, 1.76 mmol), 4-bromo-6-chloro-2-methylpyridazin-3(2H)-one (393 mg,1.76 mmol) cesium carbonate (2.00 g, 6.15 mmol) and4,5-bis(diphenylphosphino)-9,9-dimethlxanthene (152 mg, 0.26 mmol) indioxane (10 ml) was flushed with argon beforetris(dibenzylideneacetone)dipalladium(0) (121 mg, 0.13 mmol) was addedand the resulting solution was heated at 90° C. for 18 h. The mixturewas cooled to room temperature and diluted with dichloromethane (50 mL)and water. The layers were separated and the aqueous layer was extractedwith dichloromethane (2×25 mL). The organic layers were combined, driedover magnesium sulfate. The resulting mixture was filtered andconcentrated in vacuo. The precipitate formed was isolated byfiltration, washed with ether and dried under vacuum to give4-(5-(azetidin-1-ylmethyl)-1-methyl-1H-pyrazol-3-ylamino)-6-chloro-2-methylpyridazin-3(2H)-one(272 mg, 50%) as a light yellow solid.

A solution of2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate (498 mg, 1.01 mmol),4-(5-(azetidin-1-ylmethyl)-1-methyl-1H-pyrazol-3-ylamino)-6-chloro-2-methylpyridazin-3(2H)-one(183 mg, 0.59 mmol), potassium phosphate (315 mg, 1.48 mmol) anddicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (28.3 mg, 0.06mmol) in butanol (4 ml) and water (1 mL) was flushed with argon before(bis[dibenzylideneacetone] dipalladium) (17.0 mg, 0.03 mmol) was addedand the resulting solution heated at 100° C. in for 2 h. The resultingmixture was cooled, poured into a saturated solution of ammoniumchloride and extracted with methylene chloride (2×100 mL). The layerswere separated and the organic phase dried over magnesium sulfate. Themixture was filtered and concentrated in vacuo. The residue wasdissolved in dioxane (10 mL) and treated with a lithium hydroxidesolution (0.5 mL, 2.0 M), and the resulting mixture was stirred at roomtemperature overnight. The resulting mixture was poured into a saturatedammonium chloride solution and extracted with methylene chloride (2×150mL). The layers were separated and the organic phase dried overmagnesium sulfate. The mixture was filtered and concentrated in vacuo.The residue was purified by flash chromatography (silica gel, 24 g, 1%to 10% methanol in dichloromethane) to give acetic acid2-[5-(5-azetidin-1-ylmethyl-1-methyl-1H-pyrazol-3-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl]-6-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-benzylester (112 mg, 32%) as an off white solid: mp. 214-217° C.; ¹H NMR (300MHz, DMSO-d₆) δ ppm 1.01-1.55 (m, 10H) 1.72-2.08 (m, 2H) 2.90-3.67 (m,11H) 4.28-4.62 (m, 3H) 6.08 (s, 1H) 7.22-8.08 (m, 6H) 8.50 (d, J=1.89Hz, 1H) 9.15 (s, 1H).

Preparation of I-59

Example 59 Acetic acid2-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-6-[1-methyl-5-(5-methyl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazin-2-ylamino)-6-oxo-1,6-dihydro-pyridazin-3-yl]-benzylester

To a solution of 5-nitro-1H-pyrazole-3-carboxylic acid (2.0 g, 12.7mmol) in anhydrous methanol (20 ml) at to 0° C. was added thionylchloride (3.94 g, 2.42 ml, 33.1 mmol) drop wise. The resulting solutionwas heated to reflux for 2 h. The cooled solution was evaporated todryness and the residue was treated with methanol (20 ml). The resultingsolution was evaporated to dryness to give5-nitro-2H-pyrazole-3-carboxylic acid methyl ester (1.97 g, 90%) as awhite solid.

To a solution of methyl 5-nitro-1H-pyrazole-3-carboxylate (1 g, 5.84mmol) in acetone (30 mL) was added potassium carbonate (4.04 g, 29.2mmol) and 1,2-dibromoethane (3.29 g, 1.51 mL, 17.5 mmol) and theresulting solution heated to reflux for 2 h. The resulting mixture wascooled to 0° C. filtered and concentrated and the residue purified byflash chromatography (silica gel, 60 g, 20% to 40% ethyl acetate inhexanes) to give methyl1-(2-bromoethyl)-3-nitro-1H-pyrazole-5-carboxylate (1.03 g, 63%) as awhite solid.

To a solution of methyl1-(2-bromoethyl)-3-nitro-1H-pyrazole-5-carboxylate (500 mg, 1.8 mmol) intetrahydrofuran (20 mL) was cooled to 0° C. and lithium borohydride(78.3 mg, 3.6 mmol) was added in portions. The resulting mixture wasallowed to warm to room temperature overnight. To the resulting mixturewas added ethyl acetate (20 ml) and water (50 ml). The biphasic mixturewas separated and aqueous layer extracted with ethyl acetate (3×20 mL).The combined organic layers were dried over magnesium sulfate and theresulting mixture was filtered and concentrated in vacuo. The residuewas purified by flash chromatography (silica gel, AnaLogix systemSF25-40 g column, 20% to 60% ethyl acetate in hexanes) to give(1-(2-bromoethyl)-3-nitro-1H-pyrazol-5-yl)methanol (158 mg, 35%) as alight yellow oil.

To as solution of (1-(2-bromoethyl)-3-nitro-1H-pyrazol-5-yl)methanol(482 mg, 1.93 mmol) in chloroform (20 mL) was cooled to 0° C. was addedphosphorus tribromide (522 mg, 0.18 mL, 1.93 mmol) drop wise viasyringe. The resulting solution was warmed to room temperature andstirred for 1 h. The resulting solution was cooled to 0° C. and dilutedwith dichloromethane (50 ml). The resulting solution was made basic (pH8.5) with saturated aqueous sodium bicarbonate was (20 mL). The layerswere separated, and the aqueous layer was extracted with dichloromethane(3×20 mL). The combined organic layers were washed with brine (30 mL),dried over magnesium sulfate. The resulting mixture was filtered andconcentrated in vacuo to give1-(2-bromoethyl)-5-(bromomethyl)-3-nitro-1H-pyrazole (469 mg, 78%) as ayellow solid.

To a solution of 1-(2-bromoethyl)-5-(bromomethyl)-3-nitro-1H-pyrazole(469 mg, 1.5 mmol) in tetrahydrofuran (20 mL) was added methylamine(2.0M in tetrahydrofuran, 5.25 mL, 10.5 mmol) drop wise and theresulting mixture was stirred at room temperature for 76 h. The solutionwas concentrated and the resulting solid was stirred with a mixture ofethyl acetate (10 mL) and 10% aqueous potassium carbonate (10 mL). Thelayers were separated and the aqueous phase was extracted with ethylacetate (2×30 mL). The organic layers were combined and dried overmagnesium sulfate. The resulting mixture was filtered and reduced involume in vacuo and the precipitate removed by filtration. The filtratewas concentrated and the residue purified by flash chromatography(silica gel, 12 g, 2% to 10% methanol in dichloromethane) to give5-methyl-2-nitro-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazine (67 mg, 24%)as a light yellow solid.

To a solution of5-methyl-2-nitro-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazine (67 mg, 0.37mmol) in ethanol (15 mL) was treated with palladium on carbon (10%, 20mg) and flushed with argon. The resulting mixture was stirred under ahydrogen (1 atm) overnight. The reaction mixture was filtered through acelite pad, and the pad washed with ethanol. The filtrate wasconcentrated in vacuo to give5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-amine (72 mg,quantitative) as a light yellow oil.

A solution of 5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-amine(55.7 mg, 0.37 mmol), 4-bromo-6-chloro-2-methylpyridazin-3(2H)-one (81.8mg, 0.37 mmol) cesium carbonate (417 mg, 1.28 mmol) and4,5-bis(diphenylphosphino)-9,9-dimethlxanthene (31.8 mg, 0.05 mmol) indioxane (6 ml) was flushed with argon beforetris(dibenzylideneacetone)dipalladium(0) (25.1 mg, 0.03 mmol) was addedand the resulting solution was heated at 90° C. for 18 h. The mixturewas cooled to room temperature and diluted with dichloromethane (50 mL)and water. The layers were separated and the aqueous layer was extractedwith dichloromethane (2×25 mL). The organic layers were combined, driedover magnesium sulfate. The resulting mixture was filtered andconcentrated in vacuo. The residue was purified by flash chromatography(silica gel, 24 g, 2% to 7% methanol in dichloromethane) to give6-chloro-2-methyl-4-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)pyridazin-3(2H)-one(61 mg, 57%) as a light yellow solid.

A solution of2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate (153 mg, 0.31 mmol),6-chloro-2-methyl-4-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)pyridazin-3(2H)-one(61 mg, 0.21 mmol), potassium phosphate (110 mg, 0.52 mmol) anddicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (9.87 mg, 0.02mmol) in butanol (4 ml) and water (1 mL) was flushed with argon before(bis[dibenzylideneacetone] dipalladium) (5.95 mg, 0.01 mmol) was addedand the resulting solution heated at 100° C. in for 2 h. The resultingmixture was cooled, poured into a saturated solution of ammoniumchloride and extracted with methylene chloride (2×100 mL). The layerswere separated and the organic phase dried over magnesium sulfate. Themixture was filtered and concentrated in vacuo. The residue wasdissolved in dioxane (10 mL) and treated with a lithium hydroxidesolution (0.5 mL, 2.0 M), and the resulting mixture was stirred at roomtemperature overnight. The resulting mixture was poured into a saturatedammonium chloride solution and extracted with methylene chloride (2×150mL). The layers were separated and the organic phase dried overmagnesium sulfate. The mixture was filtered and concentrated in vacuo.The residue was purified by flash chromatography (silica gel, 24 g, 1%to 10% methanol in dichloromethane) to give acetic acid2-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-6-[1-methyl-5-(5-methyl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazin-2-ylamino)-6-oxo-1,6-dihydro-pyridazin-3-yl]-benzylester (56 mg, 46%) as a light yellow solid: mp. 188-193° C.; ¹H NMR (300MHz, DMSO-d₆) δ ppm 1.37 (s, 9H) 2.34 (s, 3H) 2.77 (t, J=5.29 Hz, 2H)3.50 (s, 2H) 3.63-4.06 (m, 5H) 4.17-4.67 (m, 3H) 5.98 (s, 1H) 7.33-8.05(m, 6H) 8.50 (d, J=2.64 Hz, 1H) 9.24 (s, 1H).

Preparation of I-60

Example 60 Acetic acid2-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-6-[1-methyl-5-(5-oxetan-3-yl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazin-2-ylamino)-6-oxo-1,6-dihydro-pyridazin-3-yl]-benzylester

To a solution of 5-nitro-1H-pyrazole-3-carboxylic acid (4.88 g, 31.1mmol) in anhydrous methanol (50 ml) at to 0° C. was added thionylchloride (9.61 g, 5.9 ml, 80.8 mmol) drop wise. The resulting solutionwas heated to reflux for 2 h. The cooled solution was evaporated todryness to give 5-nitro-2H-pyrazole-3-carboxylic acid methyl ester (4.58g, 86%) as a off-white solid.

To a solution of methyl 5-nitro-1H-pyrazole-3-carboxylate (5.97 g, 34.9mmol) in acetone (100 mL) was added potassium carbonate (24.1 g, 174mmol) and 1,2-dibromoethane (19.7 g, 9.02 ml, 105 mmol) and theresulting solution heated to reflux for 2 h and then stirred at roomtemperature overnight. The resulting mixture was filtered andconcentrated and the residue purified by flash chromatography (silicagel, SF65-400 g, 20% to 70% ethyl acetate in hexanes) to give methyl1-(2-bromoethyl)-3-nitro-1H-pyrazole-5-carboxylate (4.86 g, 50%) as alight yellow solid.

To a suspension of lithium borohydride (755 mg, 34.7 mmol) intetrahydrofuran (100 mL) at 0° C. was added a solution of methyl1-(2-bromoethyl)-3-nitro-1H-pyrazole-5-carboxylate (4.82 g, 17.3 mmol)in tetrahydrofuran (10 mL) drop wise maintain a temperature below 0° C.The resulting solution was allowed to stir at room temperature for 2 h.To the resulting mixture was slowly added ethyl acetate (20 ml) andwater (20 ml). The biphasic mixture was separated and aqueous layerextracted with ethyl acetate (3×20 mL). The combined organic layers weredried over magnesium sulfate and the resulting mixture was filtered andconcentrated in vacuo to give(1-(2-bromoethyl)-3-nitro-1H-pyrazol-5-yl)methanol (4.24 g, 98%) as alight yellow oil.

To a solution of (1-(2-bromoethyl)-3-nitro-1H-pyrazol-5-yl)methanol(4.24 g, 17.0 mmol) in chloroform (100 mL) was cooled to 0° C. was addedphosphorus tribromide (4.59 g, 1.6 ml, 17.0 mmol) drop wise via syringe.The resulting solution was warmed to room temperature and stirred for 2h. The resulting solution was cooled to 0° C. and diluted withdichloromethane (50 ml). The resulting solution was made basic (pH 8.5)with saturated aqueous sodium bicarbonate was (20 mL). The layers wereseparated, and the aqueous layer was extracted with dichloromethane(3×50 mL). The combined organic layers were washed with brine (30 mL),dried over magnesium sulfate. The resulting mixture was filtered andconcentrated in vacuo and the residue purified by flash chromatography(silica gel, SF40-240 g, 15% to 40% ethyl acetate in hexanes) to give1-(2-bromoethyl)-5-(bromomethyl)-3-nitro-1H-pyrazole (3.56 g, 67%) as awhite solid.

To a solution of 1-(2-bromoethyl)-5-(bromomethyl)-3-nitro-1H-pyrazole(500 mg, 1.6 mmol) in acetonitrile (20 mL) was added oxetan-3-amine (140mg, 1.92 mmol) and diisopropylethyl amine (372 mg, 0.50 ml, 2.88 mmol)drop wise and the resulting mixture was stirred at room temperature for24 h. The solution was concentrated and the residue dissolved in ethylacetate (50 mL), washed with water (50 mL) and dried over magnesiumsulfate. The resulting mixture was filtered and evaporated and theresidue purified by flash chromatography (SF25-40 g, 50% to 100% ethylacetate in hexanes) to give2-nitro-5-oxetan-3-yl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazine (255mg, 71%) as a light yellow solid.

To a solution of2-nitro-5-oxetan-3-yl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazine (255mg, 1.13 mmol) in ethanol (20 mL) was treated with palladium on carbon(10%, 60 mg) and flushed with argon. The resulting mixture was stirredunder a hydrogen (1 atm) overnight. The reaction mixture was filteredthrough a celite pad, and the pad washed with ethanol. The filtrate wasconcentrated in vacuo to give5-oxetan-3-yl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazin-2-ylamine (217mg, 99%) as a off-white solid.

A solution of5-oxetan-3-yl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazin-2-ylamine (110mg, 0.57 mmol), 4-bromo-6-chloro-2-methylpyridazin-3(2H)-one (127 mg,0.57 mmol) cesium carbonate (646 mg, 1.98 mmol) and4,5-bis(diphenylphosphino)-9,9-dimethlxanthene (49.2 mg, 0.08 mmol) indioxane (8 ml) was flushed with argon beforetris(dibenzylideneacetone)dipalladium(0) (38.9 mg, 0.04 mmol) was addedand the resulting solution was heated at 90° C. for 18 h. The mixturewas cooled to room temperature and diluted with dichloromethane (50 mL)and water. The layers were separated and the aqueous layer was extractedwith dichloromethane (2×25 mL). The organic layers were combined, driedover magnesium sulfate. The resulting mixture was filtered andconcentrated in vacuo. The precipitate formed was isolated byfiltration, washed with ether and dried under vacuum to6-chloro-2-methyl-4-(5-oxetan-3-yl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazin-2-ylamino)-2H-pyridazin-3-one(113 mg, 59%) as a light yellow solid.

A solution of2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate (249 mg, 0.50 mmol),6-chloro-2-methyl-4-(5-oxetan-3-yl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazin-2-ylamino)-2H-pyridazin-3-one(113 mg, 0.34 mmol), potassium phosphate (178 mg, 0.84 mmol) anddicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (16.0 mg, 0.03mmol) in butanol (8 ml) and water (2 mL) was flushed with argon before(bis[dibenzylideneacetone] dipalladium) (9.65 mg, 0.02 mmol) was addedand the resulting solution heated at 100° C. in for 2 h. The resultingmixture was cooled, poured into a saturated solution of ammoniumchloride and extracted with methylene chloride (2×100 mL). The layerswere separated and the organic phase dried over magnesium sulfate. Themixture was filtered and concentrated in vacuo. The residue wasdissolved in dioxane (10 mL) and treated with a lithium hydroxidesolution (0.5 mL, 2.0 M), and the resulting mixture was stirred at roomtemperature overnight. The resulting mixture was poured into a saturatedammonium chloride solution and extracted with methylene chloride (2×100mL). The layers were separated and the organic phase dried overmagnesium sulfate. The mixture was filtered and concentrated in vacuo.The residue was purified by flash chromatography (silica gel, 24 g, 1%to 10% methanol in dichloromethane) to give acetic acid2-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-6-[1-methyl-5-(5-oxetan-3-yl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazin-2-ylamino)-6-oxo-1,6-dihydro-pyridazin-3-yl]-benzylester (113 mg, 54%) as a light yellow solid: mp. 180-185° C.; ¹H NMR(300 MHz, DMSO-d₆) δ ppm 1.37 (s, 9H) 2.66-2.92 (m, 2H) 3.40-3.83 (m,6H) 3.98 (t, J=5.48 Hz, 2H) 4.26-4.82 (m, 7H) 6.01 (s, 1H) 7.36-8.00 (m,6H) 8.50 (d, J=2.64 Hz, 1H) 9.25 (s, 1H).

Preparation of I-61

Step 1. Preparation of tert-butyl4-(6-aminopyridin-3-yl)piperidine-1-carboxylate

tert-Butyl 4-(6-aminopyridin-3-yl)piperidine-1-carboxylate (3 g, 9.83mmol) in methanol (50 ml) was hydrogenated under 50 psi with 10% Pd/C(314 mg, 295 μmol) overnight. The catalyst was filtered off and thefiltrate was concentrated in vacuo to afford a colorless oil 2.73 g.(M+H)⁺=278 m/e.

Step 2. Preparation of tert-butyl4-(6-(6-chloro-2-methyl-3-oxo-2,3-dihydropyridazin-4-ylamino)pyridin-3-yl)piperidine-1-carboxylate

This reaction was carried out under similar conditions to thosedescribed in step 6 of the preparation of I-6.

A solution of 4-bromo-6-chloro-2-methylpyridazin-3(2H)-one (2.42 g, 10.8mmol), tert-butyl 4-(6-aminopyridin-3-yl)piperidine-1-carboxylate (2.73mg, 9.83 mmol), Xantphos (853 mg, 1.47 mmol) and cesium carbonate (9.61g, 29.5 mmol) in dry dioxane (80 ml) was vacuum de-gassed and placeunder an argon atmosphere. To this mixture was addedtris(dibenzylideneacetone)dipalladium (0) (203 mg, 197 mmol) and thevacuum de-gas cycle was repeated. The material was heated at 90° C. (oilbath) with vigorous stirring overnight. The flask was cooled to ambienttemperature and the contents were filtered through a plug of celite,rinsing well with dioxane, the filtrate concentrated and the resultingresidue triturated with 1; 1 ratio of ether/ethyl acetate. This providedthe desired product as an off-white powder (2.73 g, 71.2%). (M+H)+=420.2m/e.

Step 3. Preparation of tert-butyl4-(6-(6-(3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-2-(hydroxymethyl)phenyl)-2-methyl-3-oxo-2,3-dihydropyridazin-4-ylamino)pyridin-3-yl)piperidine-1-carboxylate

This reaction was carried out under similar conditions to thosedescribed above in step 7 of the preparation of Example 6. A solution oftert-butyl4-(6-(6-chloro-2-methyl-3-oxo-2,3-dihydropyridazin-4-ylamino)pyridin-3-yl)piperidine-1-carboxylate(150 mg, 357 mmol),2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate (177 mg, 357 μmol), xPhos (17 mg, 35.7 mmol) and potassiumphosphate (190 mg, 893 mmol) in 10 ml of dioxane/water (9:1) wasdegassed with nitrogen for 10 minutes andbis(dibenzylideneacetone)palladium (0) (10.3, 17.9 mmol) was added.

The reaction mixture was heated to 100° C. for 2 hr. After work up, theproduct was purified by preparative HPLC on silica gel, using a gradientof 5% to 70% ethylacetate/hexane to afford the desired product as alight yellow solid (220 mg, 81.9%).

Step 4. Preparation of tert-butyl4-(6-(6-(3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-2-(hydroxymethyl)phenyl)-2-methyl-3-oxo-2,3-dihydropyridazin-4-ylamino)pyridin-3-yl)piperidine-1-carboxylate

This reaction was carried out under similar conditions to thosedescribed above in step 8 of the preparation for I-6. After work up, thedesired product was afforded (85 mg, 40.9%).

(M+H)+=710.5 m/e.

Example 61 Step 5. Preparation of6-tert-butyl-8-fluoro-2-(2-(hydroxymethyl)-3-(1-methyl-6-oxo-5-(5-(piperidin-4-yl)pyridin-2-ylamino)-1,6-dihydropyridazin-3-yl)phenyl)phthalazin-1(2H)-one

tert-butyl4-(6-(6-(3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-2-(hydroxymethyl)phenyl)-2-methyl-3-oxo-2,3-dihydropyridazin-4-ylamino)pyridin-3-yl)piperidine-1-carboxylate(85 mg, 120 μmol) was deprotected by treatment with 50% trifluoro acidin dichloromethane (10 mL) for 2 hr. The reaction mixture wasconcentrated to dryness, then partitioned between ethyl acetate andsaturated sodium bicarbonate. The organic phase was dried over sodiumsulfate, filtered and concentrated. The resulting crude product wasfurther purified by crystallization from hot isopropylacetate/hexanes. Acrystalline product was collected by filtration, providing the desiredproduct as a white solid (48 mg, 65.7%). (M+H)+=610 m/e. ¹H NMR (300MHz, CHLOROFORM-d) δ: 8.63 (s, 1H), 8.27-8.33 (m, 2H), 8.21 (d, J=2.0Hz, 1H), 7.44-7.72 (m, 6H), 6.94 (d, J=8.5 Hz, 1H), 4.46 (s, 2H),3.88-3.96 (m, 3H), 3.35-3.44 (m, 2H), 2.85-2.99 (m, 2H), 2.65-2.78 (m,1H), 1.83-1.97 (m, 4H), 1.43 (s, 9H).

Preparation of I-62 Example 62 Preparation of6-tert-butyl-8-fluoro-2-(2-(hydroxymethyl)-3-(1-methyl-5-(5-(1-(methylsulfonyl)-piperidin-4-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)phthalazin-1(2H)-one

In a 10 mL round-bottomed flask,6-tert-butyl-8-fluoro-2-(2-(hydroxymethyl)-3-(1-methyl-6-oxo-5-(5-(piperidin-4-yl)pyridin-2-ylamino)-1,6-dihydropyridazin-3-yl)phenyl)phthalazin-1(2H)-one(35.03 mg, 57.5 μmol, Eq: 1.00) was combined with DCM (3 ml) and cooledto 0° C. DIPEA (8.91 mg, 12.0 μl, 68.9 μmol, Eq: 1.2) was added,followed by addition of methanesulfonyl chloride (6.58 mg, 4.48 μl, 57.5μmol, Eq: 1). The reaction mixture was stirred at 0° C. to roomtemperature for 1 hr. The crude material was purified by flashchromatography (silica gel, 4 g, 0% to 5% of MeOH in 50% EtOAc/Hexane)to afford white solid (16 mg, 45%). (M+H)+=688.4 m/e. ¹H NMR (300 MHz,CHLOROFORM-d) δ: 8.56 (s, 1H), 8.48 (br. s., 1H), 8.29 (br. s., 1H),8.20 (br. s., 1H), 7.42-7.70 (m, 6H), 7.04 (d, J=8.2 Hz, 1H), 4.42 (br.s., 2H), 4.11 (q, J=7.0 Hz, 2H), 3.95 (d, J=11.3 Hz, 2H), 2.82 (s, 3H),2.74-2.81 (m, 2H), 2.62 (t, J=11.5 Hz, 1H), 2.04 (s, 3H), 1.77-1.99 (m,4H), 1.42 (s, 9H).

Preparation of I-63 Step 1. Preparation of4-(5-(1-acetylpiperidin-4-yl)pyridin-2-ylamino)-6-chloro-2-methylpyridazin-3(2H)-one

In a 50 mL round-bottomed flask, tert-butyl4-(6-nitropyridin-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate (250 mg,819 μmol, Eq: 1.00) was combined with DCM (2.5 ml) to give a lightyellow solution. TFA (5 mL) was added and the resulting reaction mixturewas stirred at room temperature for 1 hr. until the reaction wascomplete as determined by LCMS. The crude reaction mixture wasconcentrated in vacuo, and the resultant residue was dissolved in DCMand cooled to 0° C. TEA (228 μl, 1.64 mmol, Eq: 2.00) was added followedby acetyl chloride (58 μl, 819 μmol, Eq: 1.00) dropwise. The reactionwas allowed to warm up to room temperature. The reaction was worked upafter half hour by extraction into ethyl acetate. The organic layer waswashed with water and sat. NH₄Cl, dried over Na₂SO₄ and concentrated todryness to afford crude product (187 mg) as off white solid.(M+H)+=247.9 m/e

This product was dissolved in methanol (15 ml) and subjected tohydrogenation at 50 psi with 10% Pd/C (87.2 mg, 819 μmol) over night.The catalyst was filtered off and the resulting filtrate wasconcentrated in vacuo and carried onto the next reaction without furtherpurification.

A solution of 4-bromo-6-chloro-2-methylpyridazin-3(2H)-one (201 mg, 901μmol), 1-(4-(6-aminopyridin-3-yl)piperidin-1-yl)ethanone (180 mg, 819μmol), Xantphos (35.5 mg, 61.4 mmol) and cesium carbonate (801 mg, 2.46mmol) in dry dioxane (6 ml) was vacuum de-gassed and place under argonatmosphere. To this mixture was addedtris(dibenzylideneacetone)dipalladium (0) (8.48 mg, 8.19 μmol) and thevacuum de-gas cycle was repeated. The material was heated at 90° C. (oilbath) with vigorous stirring overnight. The flask was cooled to ambientand the contents were filtered through a plug of celite, rinsing wellwith dioxane. The combined filtrate and washes were concentrated and theresulting residue was triturated with 1:1 ratio of ether/ethyl acetate.This provided the desired product as a off-white powder (66 mg, 22%).(M+H)+=362, 364 m/e

Example 63 Step 2. Preparation of2-(3-(5-(5-(1-acetylpiperidin-4-yl)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-(hydroxymethyl)phenyl)-6-tert-butyl-8-fluorophthalazin-1(2H)-one

This reaction was carried out under similar conditions to thosedescribed above instep 7 of preparation of Example 6. A solution of4-(5-(1-acetylpiperidin-4-yl)pyridin-2-ylamino)-6-chloro-2-methylpyridazin-3(2H)-one(66 mg, 182 μmol),2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate (90.2 mg, 182 μmol), xPhos (8.7 mg, 18.2 μmol) and potassiumphosphate (96.8 mg, 456 μmol) in 10 ml of dioxane/water (9:1) wasdegassed with nitrogen for 10 minutes andbis(dibenzylideneacetone)palladium (0) (5.24 mg, 9.12 μmol) was added.The reaction mixture was heated to 100° C. for 2 hr. After work up, theproduct was purified by preparative HPLC on silica gel, using a gradientof 0% to 5% methanol/ethyl acetate. This provided 1:1 ratio of desiredcompound and2-(5-(5-(1-acetylpiperidin-4-yl)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-6-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)benzylacetate. The resultant mixture was dissolved in methanol (4 ml) and tothis was added 2 N NaOH (468 μl). The reaction was stirred at roomtemperature for 56 h. The methanol was removed by evaporation and theresultant solution was acidified with 1N HCl and extracted with EtOAc.The organic extract was washed with water, dried over NaSO₄, filteredand concentrated in vacuo. The crude residue was purified by flashchromatography (silica gel, 4 g, 0% to 50% of MeOH in 50% EtOAc/Hexane)to afford the desired product as a white solid (61 mg, 26.2%).(M+H)+=652.5, 653.7 m/e. ¹H NMR (300 MHz, CHLOROFORM-d) δ: 8.57 (s, 1H),8.41 (br. s., 1H), 8.28 (br. s., 1H), 8.19 (br. s., 1H), 7.40-7.71 (m,6H), 6.99 (d, J=8.2 Hz, 1H), 4.80 (d, J=12.9 Hz, 1H), 4.41 (br. s., 2H),4.11 (q, J=7.0 Hz, 2H), 3.85-3.99 (m, 3H), 3.18 (t, J=12.7 Hz, 1H),2.52-2.83 (m, 2H), 2.13 (s, 3H), 1.89 (t, J=12.7 Hz, 2H), 1.60 (br. s.,2H), 1.38-1.46 (m, 9H).

Preparation of I-64 Step 1. Preparation of4-methyl-1-(6-nitropyridin-3-yl)piperidin-4-ol

4-Methylpiperidin-4-ol (2.72 g, 23.6 mmol), 5-bromo-2-nitropyridine (3.2g, 15.8 mmol), and tetrabutylammonium iodide (72 mg, 195 umol) in DMSO(20 ml) was heated to 120° C. for 18 hr. After cooling to roomtemperature, the reaction mixture was then diluted with EtOAc and washedwith water (3×20 mL). The organic phase was then concentrated andtriturated with ether to give4-methyl-1-(6-nitropyridin-3-yl)piperidin-4-ol as a yellow solid (2.55g, 68.2%). (M+H)+=327.9 m/e.

Step 2. Preparation of6-chloro-4-(5-(4-hydroxy-4-methylpiperidin-1-yl)pyridin-2-ylamino)-2-methylpyridazin-3(2H)-one

A solution of 4-methyl-1-(6-nitropyridin-3-yl)piperidin-4-ol (807 mg,3.67 mmol) in methanol (15 ml) was hydrogenated at 50 psi with 10% Pd/C(117 mg, 110 umol) overnight. The catalyst was filtered off and theresultant filtrate was concentrated in vacuo to afford1-(6-aminopyridin-3-yl)-4-methylpiperidin-4-ol. The product was carriedto next reaction without further purification.

A solution of 4-bromo-6-chloro-2-methylpyridazin-3(2H)-one (902 mg, 4.04mmol), 1-(6-aminopyridin-3-yl)-4-methylpiperidin-4-ol (761 mg, 3.67mmol), Xantphos (159 mg, 275 mmol) and cesium carbonate (3.59 g, 11mmol) in dry dioxane (10 ml) was vacuum de-gassed and placed under anargon atmosphere. To this mixture was addedtris(dibenzylideneacetone)dipalladium (0) (38 mg, 36.7 μmol) and thevacuum de-gas cycle was repeated. The material was heated at 90° C. (oilbath) with vigorous stirring overnight. The flask was cooled to ambientand the contents were filtered through a plug of celite, rinsing wellwith dioxane, and concentrating. The product was purified by preparativeHPLC on silica gel, using a gradient of 5% to 70% ethylacetate/hexane.This provided the desired product as a light yellow solid (807 mg62.9%). (M+H)+=350, 352 m/e.

Example 64 Step 3. Preparation of6-tert-butyl-8-fluoro-2-(3-(5-(5-(4-hydroxy-4-methylpiperidin-1-yl)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-(hydroxymethyl)-phenyl)phthalazin-1(2H)-one

This reaction was carried out under similar conditions to thosedescribed above instep 7 of preparation of Example 6. A solution of6-chloro-4-(5-(4-hydroxy-4-methylpiperidin-1-yl)pyridin-2-ylamino)-2-methylpyridazin-3(2H)-one(150 mg, 429 μmol),2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate (212 mg, 429 μmol), xPhos (20.4 mg, 42.9 μmol) and potassiumphosphate (228 mg, 1.07 mmol) in 10 ml of dioxane/water (9:1) wasdegassed with nitrogen for 10 minutes andbis(dibenzylideneacetone)palladium (0) (12.3 mg, 21.4 μmol) was added.The reaction mixture was heated to 100° C. for 2 hr. After work up, theproduct was purified by preparative HPLC on silica gel, using a gradientof 0% to 5% methanol/ethyl acetate. This provided 1:1 ratio of desirecompound and2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(5-(5-(4-hydroxy-4-methylpiperidin-1-yl)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)benzylacetate. The reaction mixture was dissolved in methanol (4 ml) and tothis was added 2 N NaOH (600 μA). The reaction was stirred at roomtemperature for 2 h. The methanol was removed by evaporation and theresultant solution was acidified with 1N HCl and extracted with DCM. Theresultant organic extract was dried over NaSO₄, filtered andconcentrated in vacuo. The resultant yellow solid was triturated withether to afford the desired product as an yellow solid (40 mg, 45.8%).(M+H)+=640.4 m/e. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.14-1.24 (m, 3H)1.31-1.48 (m, 12H) 1.64 (br. s., 2H) 2.35-2.68 (m, 2H) 3.31 (br. s., 2H)3.52-3.62 (m, 1H) 4.41 (d, J=11.29 Hz, 2H) 7.33-7.60 (m, 7H) 7.75 (d,J=13.30 Hz, 1H) 7.87 (s, 1H) 8.44 (br. s., 1H) 8.52 (br. s., 1H).

Preparation of I-65 Example 65

Preparation by a similar procedure to Example 64, except substitutingpiperidin-4-ol for 4-methylpiperidin-4-ol in step 1 afforded6-tert-butyl-8-fluoro-2-(2-(hydroxymethyl)-3-(5-(5-(4-hydroxypiperidin-1-yl)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)phthalazin-1(2H)-oneas a yellow solid (65 mg, 38.7%). (M+H)+=626.4 m/e. ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 1.41 (s, 9H) 1.64-1.77 (m, 2H) 1.96-2.07 (m, 2 H)2.91 (t, J=9.77 Hz, 2H) 3.39-3.53 (m, 2H) 3.80-3.91 (m, 3H) 3.97-4.04(m, 1H) 4.40 (d, J=6.64 Hz, 2H) 6.89 (d, J=8.98 Hz, 1H) 7.28 (br. s.,1H) 7.42-7.59 (m, 3H) 7.62-7.67 (m, 1H) 8.03 (br. s., 1H) 8.17 (s, 1H)8.27 (d, J=2.34 Hz, 1H) 8.45 (s, 1H).

Preparation of I-66 Step 1. Preparation of(1R,5S)-3-methyl-8-(6-nitropyridin-3-yl)-3,8-diazabicyclo[3.2.1]octane

A solution of (1R,5S)-3-Methyl-3,8-diazabicyclo[3.2.1]octanedihydrochloride (981 mg, 4.93 mmol), 5-fluoro-2-nitropyridine (100 mg,4.93 mmol), and triethylamine (4.99 g, 49.3 mmol) in DMSO (8 ml) washeated to 80° C. for 2 hr. After cooling to room temperature, thereaction mixture was diluted with EtOAc and washed with saturatedammonium chloride, and water. The organic phase was then concentratedand triturated with ether to give desire product as an yellow solid (1g, 81.8%).

Step 2. Preparation of6-chloro-2-methyl-4-(5-((1R,5S)-3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)pyridin-2-ylamino)pyridazin-3(2H)-one

This reaction was carried out under similar conditions to thosedescribed above in preparation of6-chloro-4-(5-(4-hydroxy-4-methylpiperidin-1-yl)pyridin-2-ylamino)-2-methyl-pyridazin-3(2H)-one.(1R,5S)-3-methyl-8-(6-nitropyridin-3-yl)-3,8-diazabicyclo[3.2.1]octane(500 mg, 2.01 mmol) in methanol (15 ml) was hydrogenated at 50 psi with10% Pd/C (42.9 mg, 40.3 umol) overnight. The catalyst was filtered offand the resultant filtrate was concentrated in vacuo to afford5-(3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)pyridin-2-amine. Theproduct was carried to next reaction without further purification.

A solution of 4-bromo-6-chloro-2-methylpyridazin-3(2H)-one (492 mg, 2.20mmol), 5-(3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)pyridin-2-amine(437 mg, 2.0 mmol), Xantphos (86.8 mg, 150 μmol) and cesium carbonate(1.95 g, 6.00 mmol) in dry dioxane (10 ml) was vacuum de-gassed andplace under argon atmosphere. To this mixture was addedtris(dibenzylideneacetone)dipalladium (0) (31.1 mg, 30 μmol) and thevacuum de-gas cycle was repeated. The reaction was heated at 90° C. (oilbath) with vigorous stirring overnight. The flask was cooled to ambientand the contents were filtered through a plug of celite, rinsing wellwith dioxane. The combined filtrate and washes were concentrated. Theresultant crude residue was triturated with ether to provide the desiredproduct as a light yellow solid (345 mg, 47.8%).

(M+H)+=361.0, 363 m/e.

Example 66 Step 3. Preparation of6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-((1R,5S)-3-methyl-3,8-diaza-bicyclo[3.2.1]oct-8-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one

This reaction was carried out under similar conditions to thosedescribed above instep 7 of preparation of Example 6. A solution of6-chloro-2-methyl-4-(5-((1R,5S)-3-methyl-3,8-diazabicyclo[3.2.1]-octan-8-yl)pyridin-2-ylamino)pyridazin-3(2H)-one(150 mg, 416 μmol),2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate (206 mg, 416 μmol), xPhos (19.8 mg, 41.6 μmol) and potassiumphosphate (221 mg, 1.04 mmol) in 10 ml of dioxane/water (9:1) wasdegassed with nitrogen for 10 minutes andbis(dibenzylideneacetone)palladium (0) (12.0 mg, 20.8 μmol) was added.The reaction mixture was heated to 100° C. for 2 hr. After work up, theproduct was purified by preparative HPLC on silica gel, using a gradientof 10% to 20% methanol/dichloromethane to afford2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(1-methyl-5-(5-(3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridazin-3-yl)benzylacetate as light yellow solid (69 mg, 24%). %). (M+H)+=693, 694 m/e.

The2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(1-methyl-5-(5-(3-methyl-3,8-diazabi-cyclo[3.2.1]octan-8-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridazin-3-yl)benzylacetate (55 mg, 79 μmol) was dissolved in MeOH (3 ml) and to this wasadded 2 N NaOH (794 μl). The reaction was stirred at room temperaturefor 18 h. The crude reaction was extracted with DCM. The resultantorganic extract was dried over NaSO₄, filtered and concentrated invacuo. and triturated with ether to afford desired product as an yellowsolid (10.3 mg, 20%).

(M+H)+=651.5, 652.6 m/e. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.41 (s,9H) 1.59 (d, J=11.72 Hz, 1H) 1.93-2.07 (m, 2H) 2.16-2.35 (m, 2H) 3.88(s, 3H) 3.95-4.04 (m, 1H) 4.09-4.20 (m, 2H) 4.40 (d, J=7.03 Hz, 2H)5.17-5.40 (m, 3H) 6.90 (d, J=8.98 Hz, 1H) 7.12 (dd, J=8.98, 2.73 Hz, 2H)7.41-7.59 (m, 10H) 7.65 (d, J=7.81 Hz, 2H) 7.91 (d, J=2.73 Hz, 2 H) 8.12(s, 2H) 8.25-8.31 (m, 2H) 8.40 (s, 2H).

Preparation of I-67 Step 1. Preparation of6-Chloro-4-(1′,2′,3′,4′,5′,6′-hexahydro-[3,4]bipyridinyl-6-ylamino)-2-methyl-2H-pyridazin-3-one

tert-Butyl4-(6-(6-chloro-2-methyl-3-oxo-2,3-dihydropyridazin-4-ylamino)pyridin-3-yl)piperidine-1-carboxylate,which was prepared as described in example 29, steps 1-3 (1.8 g, 4.3mmol) was dissolved in 15 mL DCM and treated with 7.5 mL TFA. Thereaction mixture was stirred at room temperature for 1 h. The crudereaction mixture was concentrated in vacuo. The resulting residue wasdiluted with DCM and sat. NaHCO₃ and extracted with DCM. The extractswere dried over Na₂SO₄ and concentrated in vacuo. to afford 620 mg ofthe desired product which was carried on as is to the next step.

Step 2. Preparation of6-Chloro-2-methyl-4-(1′-methyl-1′,2′,3′,4′,5′,6′-hexahydro-[3,4]bipyridinyl-6-ylamino)-2H-pyridazin-3-one

In a 25 mL round-bottomed flask,6-chloro-2-methyl-4-(5-(piperidin-4-yl)pyridin-2-ylamino)pyridazin-3(2H)-one(620 mg, 1.94 mmol, Eq: 1.00) and formaldehyde (1.57 g, 1.44 ml, 19.4mmol, Eq: 10) were combined with THF to give a light yellow solution.Acetic acid (116 mg, 111 μl, 1.94 mmol, Eq: 1.00) was added. Thereaction mixture was cooled to 0° C. Sodium triacetoxyborohydride (616mg, 2.91 mmol, Eq: 1.5) was added. The reaction mixture was stirred atroom temperature 2 hr. LC/MS showed reaction was complete. The reactionmixture was poured into water. Saturated NaHCO₃ was added to make itbasic and the resultant mixture was extracted with EtOAc. The combinedextracts were washed with water, dried over Na₂SO₄ and concentrated invacuo. The resultant solid was triturated with ether to afford thedesired product as an off-white solid (580 mg). (M+H)+=334 m/e. This wascombined with previous batches to give 1.06 g6-chloro-2-methyl-4-(1′-methyl-1′,2′,3′,4′,5′,6′-hexahydro-[3,4]bipyridinyl-6-ylamino)-2H-pyridazin-3-one,which was carried on as is into the next reaction.

Example 67 Step 3. Preparation of6-tert-Butyl-8-fluoro-2-{2-hydroxymethyl-3-[1-methyl-5-(1′-methyl-1′,2′,3′,4′,5′,6′-hexahydro-[3,4]bipyridinyl-6-ylamino)-6-oxo-1,6-dihydro-pyridazin-3-yl]-phenyl}-2H-phthalazin-1-one

A mixture of6-chloro-2-methyl-4-(5-(1-methylpiperidin-4-yl)pyridin-2-ylamino)pyridazin-3(2H)-one(1.06 g, 3.18 mmol), potassium(2-(acetoxymethyl)-3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)phenyl)trifluoroborate(1.51 g, 3.18 mmol), xPhos (227 mg, 476 μmol) and potassium phosphate(1.48 g, 6.99 mmol) in 60 ml of butanol/water (5:1) was degassed withnitrogen for 10 minutes and bis(dibenzylideneacetone)palladium (0) (137mg, 238 mmol) was added. The reaction mixture was heated to 110° C. for3 hr. The crude reaction mixture was extracted with DCM, washed withwater, dried over Na₂SO₄, filtered and concentrated to form a solidduring concentration. This solid was triturated with ether to afford1.67 g of crude product. Combined with 300 mg of crude material from aprevious batch and purified by silica chromatography to afford2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(1-methyl-5-(5-(1-methylpiperidin-4-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridazin-3-yl)benzylacetate (1.6 g) as a white solid.

2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(1-methyl-5-(5-(1-methylpiperidin-4-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridazin-3-yl)benzylacetate (1.6 g) was dissolved in 20 mL THF. To the reaction solution wasadded 12 mL of 2 N NaOH. The reaction mixture was stirred at roomtemperature overnight. Reaction was not complete. An additional 10equiv. of 2 N NaOH was added and the reaction mixture was stirred atroom temperature for an additional 2 hours. THF was added until thereaction mixture was homogeneous and the reaction was heated to 40° C.for 30 min. The reaction was allowed to cool to room temperature andstirred overnight. The reaction had gone to completion as indicated byLC/MS. The reaction was concentrated to a reduced volume to remove mostof the THF. A solid formed which was collected by filtration. The solidwas redissolved in DCM, filtered through pack of celite, washed withwater, dried over Na₂SO₄, filtered and conc in vacuo. to afford thedesired product as a white solid (1.27 g). (M+H)+=624 m/e. ¹H NMR (400MHz, CHLOROFORM-d) δ ppm 1.45 (s, 9H) 1.80-1.92 (m, 5H) 2.31-2.58 (m,3H) 3.03 (d, J=8.28 Hz, 1H) 3.92 (s and overlapping multiplet, 4H) 4.45(d, J=6.53 Hz, 2H) 6.93 (d, J=8.28 Hz, 1H) 7.45-7.63 (m, 5H) 7.65-7.71(m, 1H) 8.22-8.32 (m, 3H) 8.61 (s, 1H).

Preparation of I-68

Example 68 Preparation of6-tert-Butyl-2-(3-{5-[1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-2-hydroxymethyl-phenyl)-8-fluoro-2H-phthalazin-1-one

A solution of(R)-1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1H-pyrazol-3-amine(prepared as in WO2009127546(A1), Example 49, 177 mg, 0.90 mmol),4-bromo-6-chloro-2-methylpyridazin-3(2H)-one (200 mg, 0.90 mmol) cesiumcarbonate (1.02 g, 3.13 mmol) and4,5-bis(diphenylphosphino)-9,9-dimethlxanthene (77.7 mg, 0.134 mmol) indioxane (10 ml) was flushed with argon beforetris(dibenzylideneacetone)dipalladium(0) (61.5 mg, 0.07 mmol) was addedand the resulting solution was heated at 90° C. for 18 h. The mixturewas cooled to room temperature and diluted with dichloromethane andwater. The layers were separated and the aqueous layer was extractedwith dichloromethane. The organic layers were combined, dried overmagnesium sulfate. The resulting mixture was filtered and concentratedin vacuo. The residue was purified by flash chromatography (silica gel,24 g, 0% to 10% methanol/dichloromethane) to give(R)-6-chloro-4-(1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1H-pyrazol-3-ylamino)-2-methylpyridazin-3(2H)-one(249 mg, 82%) as a yellow solid.

A solution of2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate (247 mg, 0.50 mmol),6-chloro-2-methyl-4-(5-oxetan-3-yl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazin-2-ylamino)-2H-pyridazin-3-one(100 mg, 0.29 mmol), potassium phosphate (156 mg, 0.74 mmol) anddicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (14.0 mg, 0.03mmol) in butanol (4 ml) and water (1 mL) was flushed with argon before(bis[dibenzylideneacetone] dipalladium) (8.46 mg, 0.01 mmol) was addedand the resulting solution heated at 100° C. in for 2 h. The resultingmixture was cooled, poured into a saturated solution of ammoniumchloride and extracted with methylene chloride (2×100 mL). The layerswere separated and the organic phase dried over magnesium sulfate. Themixture was filtered and concentrated in vacuo. The residue wasdissolved in dioxane (10 mL) and treated with a lithium hydroxidesolution (1 mL, 2.0 M), and the resulting mixture was stirred at roomtemperature overnight. The resulting mixture was poured into a saturatedammonium chloride solution and extracted with methylene chloride (2×150mL). The layers were separated and the organic phase dried overmagnesium sulfate. The mixture was filtered and concentrated in vacuo.The residue was purified by flash chromatography (silica gel, 40 g, 2%to 10% methanol in dichloromethane) to give acetic acid2-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-6-[1-methyl-5-(5-oxetan-3-yl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazin-2-ylamino)-6-oxo-1,6-dihydro-pyridazin-3-yl]-benzylester (138 mg, 72%) as a light yellow solid.

To a solution of(R)-6-tert-butyl-2-(3-(5-(1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1H-pyrazol-3-ylamino)-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-(hydroxymethyl)phenyl)-8-fluorophthalazin-1(2H)-one(135 mg, 0.21 mmol) in tetrahydrofuran (4 ml) was added a solution ofhydrochloric acid (1.0 N, 4 ml) and the resulting solution was stirredat room temperature overnight. The resulting mixture was poured into asaturated aqueous ammonium chloride solution and extracted withdichloromethane (2×50 mL). The organic layers were combined and driedover magnesium sulfate. The mixture was filtered and evaporated and theresidue crystallized from dichloromethane and isopropyl acetate. Thecrystals were washed with ether and dried to give6-tert-butyl-2-(3-{5-[1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-2-hydroxymethyl-phenyl)-8-fluoro-2H-phthalazin-1-one(52 mg, 41%) as a light yellow solid: mp. 245-250° C.; ¹H NMR (300 MHz,DMSO-d₆) δ ppm 1.38 (s, 9H) 3.67-4.24 (m, 6H) 4.27-5.06 (m, 5H) 6.19 (d,J=2.27 Hz, 1H) 7.18-7.96 (m, 7H) 8.51 (d, J=2.27 Hz, 1H) 9.23 (s, 1H).

Preparation of I-69

Example 69 Preparation of6-tert-Butyl-2-(3-{5-[5-(4-ethyl-piperazin-1-yl)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-2-hydroxymethyl-phenyl)-8-fluoro-2H-phthalazin-1-one

To a solution of 1-ethyl-4-(6-nitropyridin-3-yl)piperazine (500 mg, 2.12mmol) in ethanol (20 mL) was added 10% Pd/C (113 mg, 0.11 mmol) and theresulting mixture was stirred under a hydrogen atmosphere for 18 h. Thereaction mixture was filtered through celite, washed with ethanol andconcentrated to giveN-[(E)-2-(4-ethyl-piperazin-1-yl)-penta-2,4-dien-(Z)-ylidene]-methanediamine(377 mg, 86%) as a grey solid.

A solution of 5-(4-ethylpiperazin-1-yl)pyridin-2-amine (185 mg, 0.90mmol), 4-bromo-6-chloro-2-methylpyridazin-3(2H)-one (200 mg, 0.90 mmol)cesium carbonate (1.02 g, 3.13 mmol) and4,5-bis(diphenylphosphino)-9,9-dimethlxanthene (77.7 mg, 0.13 mmol) indioxane (10 ml) was flushed with argon beforetris(dibenzylideneacetone)dipalladium(0) (61.5 mg, 0.07 mmol) was addedand the resulting solution was heated at 90° C. for 18 h. The mixturewas cooled to room temperature and diluted with dichloromethane andwater. The layers were separated and the aqueous layer was extractedwith dichloromethane (2×25 mL). The organic layers were combined, driedover magnesium sulfate. The resulting mixture was filtered andconcentrated in vacuo. The residue was triturated with methanol anddichloromethane and filtered, washed with ether and dried to give6-chloro-4-[5-(4-ethyl-piperazin-1-yl)-pyridin-2-ylamino]-2-methyl-2H-pyridazin-3-one(138 mg, 44%) as a yellow solid.

A solution of2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate (241 mg, 0.49 mmol),6-chloro-4-(5-(4-ethylpiperazin-1-yl)pyridin-2-ylamino)-2-methylpyridazin-3(2H)-one(100 mg, 0.29 mmol), potassium phosphate (152 mg, 0.72 mmol) anddicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (13.7 mg, 0.03mmol) in butanol (4 ml) and water (1 mL) was flushed with argon before(bis[dibenzylideneacetone] dipalladium) (8.24 mg, 0.01 mmol) was addedand the resulting solution heated at 100° C. in for 2 h. The resultingmixture was cooled, poured into a saturated solution of ammoniumchloride and extracted with methylene chloride (2×100 mL). The layerswere separated and the organic phase dried over magnesium sulfate. Themixture was filtered and concentrated in vacuo. The residue wasdissolved in dioxane (10 mL) and treated with a lithium hydroxidesolution (0.5 mL, 2.0 M), and the resulting mixture was stirred at roomtemperature overnight. The resulting mixture was poured into a saturatedammonium chloride solution and extracted with methylene chloride (2×50mL). The layers were separated and the organic phase dried overmagnesium sulfate. The mixture was filtered and concentrated in vacuo.The residue was purified by flash chromatography (silica gel, 24 g, 1%to 14% methanol in dichloromethane) and recrystallized fromdichloromethane and isopropyl acetate to give6-tert-Butyl-2-(3-{5-[5-(4-ethyl-piperazin-1-yl)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-2-hydroxymethyl-phenyl)-8-fluoro-2H-phthalazin-1-one(47 mg, 26%) as a light yellow solid: mp 245-247° C.; ¹H NMR (300 MHz,DMSO-d₆) δ ppm 1.02 (t, J=7.18 Hz, 4H) 1.38 (s, 10H) 2.13-2.42 (m, 2H)3.09 (br. s., 5H) 3.77 (s, 3H) 4.16-4.72 (m, 3H) 7.20-8.10 (m, 9H)8.28-8.64 (m, 2H) 9.23 (s, 1H).

Preparation of I-70 Example 70 Preparation of6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{5-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one

A solution of 1-(3-amino-1H-pyrazol-1-yl)-2-methylpropan-2-ol (preparedas in U.S. Pat. No. 7,935,699 B2, Example 74, 139 mg, 0.90 mmol),4-bromo-6-chloro-2-methylpyridazin-3(2H)-one (200 mg, 0.90 mmol) cesiumcarbonate (1.02 g, 3.13 mmol) and4,5-bis(diphenylphosphino)-9,9-dimethlxanthene (77.7 mg, 0.13 mmol) indioxane (10 ml) was flushed with argon beforetris(dibenzylideneacetone)dipalladium(0) (61.5 mg, 0.07 mmol) was addedand the resulting solution was heated at 90° C. for 18 h. The mixturewas cooled to room temperature and diluted with dichloromethane andwater. The layers were separated and the aqueous layer was extractedwith dichloromethane. The organic layers were combined, dried overmagnesium sulfate. The resulting mixture was filtered and concentratedin vacuo. The residue was purified by flash chromatography (silica gel,24 g, 0% to 10% methanol in dichloromethane) to give6-chloro-4-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-ylamino]-2-methyl-2H-pyridazin-3-one(156 mg, 59%) as a light yellow solid.

A solution of2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate (282 mg, 0.57 mmol),6-chloro-4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-3-ylamino)-2-methylpyridazin-3(2H)-one(100 mg, 0.34 mmol), potassium phosphate (178 mg, 0.84 mmol) anddicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (16.0 mg, 0.03mmol) in butanol (4 ml) and water (1 mL) was flushed with argon before(bis[dibenzylideneacetone] dipalladium) (9.66 mg, 0.02 mmol) was addedand the resulting solution heated at 100° C. in for 2 h. The resultingmixture was cooled, poured into a saturated solution of ammoniumchloride and extracted with methylene chloride (2×100 mL). The layerswere separated and the organic phase dried over magnesium sulfate. Themixture was filtered and concentrated in vacuo. The residue wasdissolved in dioxane (10 mL) and treated with a lithium hydroxidesolution (0.5 mL, 2.0 M), and the resulting mixture was stirred at roomtemperature overnight. The resulting mixture was poured into a saturatedammonium chloride solution and extracted with methylene chloride (2×150mL). The layers were separated and the organic phase dried overmagnesium sulfate. The mixture was filtered and concentrated in vacuo.The residue was purified by flash chromatography (silica gel, 24 g, 1%to 10% methanol in dichloromethane) to give6-tert-butyl-8-fluoro-2-(2-hydroxymethyl-3-{5-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one(119 mg, 60%) as a white solid: MP. 165-170° C.; ¹H NMR (300 MHz,DMSO-d₆) δ ppm 0.91-1.13 (m, 6H) 1.38 (s, 8H) 3.16-3.36 (m, 2H) 3.91 (s,2H) 4.35-4.65 (m, 4H) 6.20 (d, J=2.27 Hz, 1H) 7.28-7.64 (m, 4H) 7.75 (d,J=13.22 Hz, 1H) 7.82-7.99 (m, 2H) 8.51 (d, J=2.27 Hz, 1H) 9.24 (s, 1H).

Preparation of I-71 Example 71

2-(8-Fluoro-2-{2-hydroxymethyl-3-[1-methyl-5-(1′-methyl-1′,2′,3′,4′,5′,6′-hexahydro-[3,4′]bipyridinyl-6-ylamino)-6-oxo-1,6-dihydro-pyridazin-3-yl]-phenyl}-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-methyl-propionitrilewas prepared using the general procedure described for compound I-15,but substituting6-Chloro-2-methyl-4-(1′-methyl-1′,2′,3′,4′,5′,6′-hexahydro-[3,4]bipyridinyl-6-ylamino)-2H-pyridazin-3-onefor6-chloro-2-methyl-4-(5-morpholine-4-carbonyl)pyridine-2-ylamino)pyridazin-3(2H)-onein step 11 to provide 106 mg of final product as a light yellow powder.(M+H)⁺=634 m/e, ¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.81 (s, 6H)1.82-1.90 (m, 4H) 2.02-2.22 (m, 2H) 2.36 (s, 3H) 2.41-2.60 (m, 1H)2.91-3.12 (m, 2H) 3.91 (s, 3H) 3.96-4.09 (m, 1H) 4.23-4.49 (m, 2H) 6.61(dd, J=7.55, 1.89 Hz, 1H) 6.91 (d, J=8.31 Hz, 1H) 7.21 (dd, J=12.09,1.89 Hz, 1H) 7.35 (d, J=7.55 Hz, 1H) 7.42 (dd, J=7.74, 1.32 Hz, 1H)7.50-7.55 (m, 2H) 7.59 (t, J=7.74 Hz, 1H) 7.67 (dd, J=7.93, 1.51 Hz, 1H)8.23 (d, J=2.27 Hz, 1H) 8.28 (s, 1H) 8.62 (s, 1H).

Preparation of I-72 Example 72

2-(2-{3-[5-(5-Azetidin-1-ylmethyl-1-methyl-1H-pyrazol-3-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl]-2-hydroxymethyl-phenyl}-8-fluoro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-methyl-propionitrilewas prepared using the general procedure described for compound I-15,but substituting4-(5-azetidin-1-ylmethyl-1-methyl-1H-pyrazol-3-ylamino)-6-chloro-2-methyl-2H-pyridazin-3-onefor6-chloro-2-methyl-4-(5-morpholine-4-carbonyl)pyridine-2-ylamino)pyridazin-3(2H)-onein step 11 to provide 471 mg of final product as an off-white powder.(M+H)⁺=609 m/e, ¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.81 (s, 6H) 2.12(quin, J=7.20 Hz, 2H) 3.27 (t, J=7.0 Hz, 4H) 3.55 (s, 2H) 3.81 (s, 3H)3.88 (s, 3H) 4.03-4.19 (m, 1H) 4.22-4.44 (m, 2H) 5.94 (s, 1H) 6.61 (dd,J=7.36, 2.08 Hz, 1H) 7.21 (dd, J=12.09, 1.89 Hz, 1H) 7.35 (d, J=7.55 Hz,1H) 7.41 (dd, J=7.74, 1.32 Hz, 1H) 7.52 (d, J=1.51 Hz, 1H) 7.56 (t,J=7.74 Hz, 1H) 7.65 (dd, J=7.55, 1.51 Hz, 1H) 7.82 (s, 1H) 7.91 (s, 1H).

Preparation of I-73 Example 73

2-[2-(3-{5-[5-(2-Azetidin-1-yl-1,1-dimethyl-ethoxy)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-2-hydroxymethyl-phenyl)-8-fluoro-1-oxo-1,2-dihydro-isoquinolin-6-yl]-2-methyl-propionitrilewas prepared using the general procedure described for compound I-15,but substituting4-[5-(2-azetidin-1-yl-1,1-dimethyl-ethoxy)-pyridin-2-ylamino]-6-chloro-2-methyl-2H-pyridazin-3-onefor6-chloro-2-methyl-4-(5-morpholine-4-carbonyl)pyridine-2-ylamino)pyridazin-3(2H)-onein step 11. The resultant Suzuki product was carried through theremaining step 12 of the synthesis to provide 143 mg of final product asa light yellow powder.

(M+H)⁺=664 m/e, ¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.24 (s, 6H) 1.81(s, 6H) 2.12 (quin, J=6.80 Hz, 2H) 2.59 (s, 2H) 3.35 (t, J=6.99 Hz, 4H)3.91 (s, 3H) 3.95-4.06 (m, 1 H) 4.25-4.44 (m, 2H) 6.61 (dd, J=7.37, 2.08Hz, 1H) 6.89 (d, J=8.69 Hz, 1H) 7.21 (dd, J=12.28, 1.70 Hz, 1H) 7.33(dd, J=8.69, 2.64 Hz, 2H) 7.34 (d, J=7.18 Hz, 1H) 7.42 (dd, J=7.74, 1.32Hz, 1H) 7.53 (d, J=1.89 Hz, 1H) 7.59 (t, J=7.74 Hz, 1H) 7.68 (dd,J=7.93, 1.51 Hz, 1H) 8.08 (d, J=2.64 Hz, 1H) 8.27 (s, 1H) 8.55 (s, 1H)

Preparation of I-74 Example 74

2-(8-Fluoro-2-{2-hydroxymethyl-3-[1-methyl-5-(5-methyl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazin-2-ylamino)-6-oxo-1,6-dihydro-pyridazin-3-yl]-phenyl}-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-methyl-propionitrilewas prepared using the general procedure described for compound I-15,but substituting6-chloro-2-methyl-4-(5-methyl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazin-2-ylamino)-2H-pyridazin-3-onefor6-chloro-2-methyl-4-(5-morpholine-4-carbonyl)pyridine-2-ylamino)pyridazin-3(2H)-onein step 11 to provide 29 mg of final product as a light yellow powder.

(M+H)⁺=595 m/e, ¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.80 (s, 6H) 2.49(s, 3H) 2.90 (t, J=5.70 Hz, 2H) 3.61 (s, 2H) 3.88 (s, 3H) 4.04-4.11 (m,1H) 4.10 (t, J=5.70 Hz, 2H) 4.24-4.42 (m, 2H) 5.78 (s, 1H) 6.61 (dd,J=7.37, 2.08 Hz, 1H) 7.21 (dd, J=12.09, 1.89 Hz, 1H) 7.34 (d, J=7.55 Hz,1H) 7.40 (dd, J=7.74, 1.32 Hz, 1H) 7.52 (d, J=1.89 Hz, 1H) 7.55 (t,J=7.93 Hz, 1H) 7.65 (dd, J=7.93, 1.51 Hz, 1H) 7.84 (s, 1H) 7.98 (s, 1H).

Preparation of I-75 Example 75

6-(6-{3-[6-(Cyano-dimethyl-methyl)-8-fluoro-1-oxo-1H-isoquinolin-2-yl]-2-hydroxymethyl-phenyl}-2-methyl-3-oxo-2,3-dihydro-pyridazin-4-ylamino)-N,N-dimethyl-nicotinamidewas prepared using the general procedure described for compound I-15,but substituting6-(6-chloro-2-methyl-3-oxo-2,3-dihydro-pyridazin-4-ylamino)-N,N-dimethyl-nicotinamidefor6-chloro-2-methyl-4-(5-morpholine-4-carbonyl)pyridine-2-ylamino)pyridazin-3(2H)-onein step 11 to provide 246 mg of final product as a white powder.(M+H)⁺=608 m/e, ¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.80 (s, 6H) 3.11(s, 6H) 3.85-3.91 (m, 1H) 3.92 (s, 3H) 4.26-4.46 (m, 2H) 6.62 (dd,J=7.55, 1.89 Hz, 1H) 6.98 (d, J=8.69 Hz, 1H) 7.21 (dd, J=12.28, 1.70 Hz,1H) 7.34 (d, J=7.55 Hz, 1H) 7.42 (m, 1H) 7.53 (d, J=1.51 Hz, 1H) 7.60(t, J=7.74 Hz, 1H) 7.65-7.72 (m, 1H) 7.79 (dd, J=8.69, 2.27 Hz, 1H) 8.44(s, 1H) 8.47 (d, J=2.27 Hz, 1H) 8.71 (s, 1H).

Preparation of I-76 Example 76

2-[8-Fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-((S)-1-methyl-pyrrolidin-2-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-1-oxo-1,2-dihydro-isoquinolin-6-yl]-2-methyl-propionitrilewas prepared using the general procedure described for compound I-15,but substituting6-chloro-2-methyl-4-[5-((S)-1-methyl-pyrrolidin-2-yl)-pyridin-2-ylamino]-2H-pyridazin-3-onefor6-chloro-2-methyl-4-(5-morpholine-4-carbonyl)pyridine-2-ylamino)pyridazin-3(2H)-onein step 11 to provide 107 mg of final product as a white powder.

(M+H)⁺=620 m/e, ¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.65-1.79 (m, 1H),1.80 (s 3H) 1.81-2.06 (m, 3H) 2.17 (d, J=1.89 Hz, 3H) 2.23-2.37 (m, 2H)2.99-3.11 (m, 1H) 3.18-3.31 (m, 1H) 3.91 (s, 3H) 3.96-4.09 (m, 1H)4.26-4.44 (m, 2H) 6.61 (dd, J=7.37, 2.08 Hz, 1H) 6.95 (d, J=8.31 Hz, 1H)7.21 (dd, J=12.46, 1.89 Hz, 1H) 7.35 (d, J=7.55 Hz, 1H) 7.42 (dd,J=7.93, 1.13 Hz, 1H) 7.52 (d, J=1.89 Hz, 1H) 7.58 (t, J=7.74 Hz, 1H)7.65-7.73 (m, 2H) 8.24-8.28 (m, 1H) 8.30 (s, 1H) 8.67 (s, 1H).

Preparation of I-77 Example 77

2-[8-Fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-((S)-1-methyl-pyrrolidin-3-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-1-oxo-1,2-dihydro-isoquinolin-6-yl]-2-methyl-propionitrilewas prepared using the general procedure described for compound I-15,but substituting6-chloro-2-methyl-4-[5-((S)-1-methyl-pyrrolidin-3-yl)-pyridin-2-ylamino]-2H-pyridazin-3-onefor6-chloro-2-methyl-4-(5-morpholine-4-carbonyl)pyridine-2-ylamino)pyrid-azin-3(2H)-onein step 11 to provide 18 mg of final product as a light yellow powder.

(M+H)⁺=620 m/e, ¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.81 (s, 6H)1.82-1.91 (m, 1H) 2.29-2.40 (m, 1H) 2.42 (s, 3H) 2.47-2.52 (m, 1H)2.63-2.82 (m, 2H) 2.91-3.02 (m, 1 H) 3.31-3.40 (m, 1H) 3.90 (s, 3H)4.23-4.47 (m, 2H) 6.61 (dd, J=7.55, 1.89 Hz, 1H) 6.92 (d, J=8.31 Hz, 1H)7.21 (dd, J=12.09, 1.89 Hz, 1H) 7.35 (d, J=7.18 Hz, 1H) 7.42 (dd,J=7.74, 1.32 Hz, 1H) 7.52 (d, J=1.51 Hz, 1H) 7.54-7.65 (m, 2H) 7.65-7.71(m, 1H) 8.25 (d, J=2.64 Hz, 1H) 8.28 (s, 1H) 8.63 (s, 1H)

This example illustrates the synthesis of“2-[2-(3-{5-[5-(2-azetidin-1-yl-1,1-dimethyl-ethoxy)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-2-hydroxymethyl-phenyl)-8-fluoro-1-oxo-1,2,3,4-tetrahydro-isoquinolin-6-yl]-2-methyl-propionitrile.

Step 1. Preparation of 6,8-difluoro-3,4-dihydro-2H-isoquinolin-1-one

A 1000 ml 3-neck round bottom flask, fitted with an overhead stirrer,was charged with 5,7-difluoro-2,3-dihydro-1H-indene-1-one (10 g, 59.4mmol) followed by dry dichloromethane (100 ml) and methanesulfonic acid(71.3 ml, 1.1 mol). The reaction was cooled to 0° C. (ice bath) and tothis was added sodium azide (5.41 g; 83.2 mmol) in 4 equal portions over20 minutes. The reaction was stirred at 0° C. for 2 hours and then a 20%aqueous solution of sodium hydroxide (175 ml) was added over 30 minuteswith vigorous stirring. After complete addition the mixture wastransferred to a separatory funnel and the methylene chloride phase wasisolated. This was shaken with an equal volume of 50% diluted brinesolution. The organic phase was collected and the aqueous phases wereback extracted with dichloromethane (2×80 ml). The organic phases werecombined, dried (magnesium sulfate), filtered and concentrated in vacuo.The crude residue was purified via HPLC on silica gel, eluting with 40%to 95% ethyl acetate/hexanes to provide the desired product as a whitesolid (8.364 g). (M+H)⁺=184 m/e.

Step 2. Preparation of2-(8-fluoro-1-oxo-1,2,3,4-tetrahydro-isoquinolin-6-yl)-2-methyl-propionitrile

To a flask containing a solution of6,8-difluoro-3,4-dihydro-2H-isoquinolin-1-one (4 g, 21.8 mmol) andisobutyronitrile (6.04 g, 87.4 mmol) in dry tetrahydrofuran (45 ml) wasadded a solution of potassium bis(trimethylsily)amide (50.4 ml, 0.91M intetrahydrofuran) and the mixture was placed in an oil bath and heated to70° C. On heating a red-brown homogeneous solution was obtained within 5minutes. After 1 hour at 70° C., additional potassiumbis(trimethylsily)amide (5 ml of 0.91 M) was added and was stirringcontinued for another 30 minutes. The flask was cooled to ambienttemperature and the reaction was quenched with water (125 ml). Ethylacetate (100 ml) was added and the material was transferred to aseparatory funnel. The organic phase was collected and the aqueous phasewas back extracted with ethyl acetate (2×70 ml). The combined organicphases were dried over magnesium sulfate, filtered and concentrated invacuo. The residue was purified by chromatography on silica gel elutingwith 100% dichloromethane to 3% methanol/dichloromethane to provide asemi-pure component (710 mg, 33% purity) as well as pure product as awhite powder (316 mg). (M+H)⁺=233 m/e.

Step 3. Preparation of242-(3-bromo-2-formyl-phenyl)-8-fluoro-1-oxo-1,2,3,4-tetrahydro-isoquinolin-6-yl]-2-methyl-propionitrile

This reaction was carried out under similar conditions to thosedescribed in step 10, example I-15 (Scheme D). After workup the productwas purified by HPLC on silica gel, eluting with a gradient of 100%methylene chloride to 1% methanol/methylene chloride. This provided thedesired product as a light yellow solid (278 mg). (M+H)⁺=415/417 m/e.

Step 4. Preparation of2-[2-(3-{5-[5-(2-azetidin-1-yl-1,1-dimethyl-ethoxy)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-2-hydroxymethyl-phenyl)-8-fluoro-1-oxo-1,2,3,4-tetrahydro-isoquinolin-6-yl]-2-methyl-propionitrile

This reaction was carried out under similar conditions to thosedescribed in step 11, example I-15 (Scheme D), but substituting4-[5-(2-azetidin-1-yl-1,1-dimethyl-ethoxy)-pyridin-2-ylamino]-6-chloro-2-methyl-2H-pyridazin-3-onefor6-Chloro-2-methyl-4-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-2H-pyridazin-3-one.After work-up the product was purified by HPLC on silica gel, elutingwith a gradient of 100% methylenechloride to 1%methanol/methylenechloride. This provided the desired product as a lightbrown solid (172 mg). (M+H)⁺=664 m/e.

Preparation of I-78 Example 78 Step 5. Preparation of2-[2-(3-{5-[5-(2-azetidin-1-yl-1,1-dimethyl-ethoxy)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-2-hydroxymethyl-phenyl)-8-fluoro-1-oxo-1,2,3,4-tetrahydro-isoquinolin-6-yl]-2-methyl-propionitrile

This reaction was carried out under similar conditions to thosedescribed in step 12, example I-15 (Scheme D). After work-up the productwas purified by HPLC on silica gel, eluting with a gradient of 3% to 14%methanol/methylene chloride. This material was then crystallized fromhot methylene chloride/hexanes to provide the desired product as a whitesolid (108 mg). (M+H)⁺=666 m/e. ¹H NMR (300 MHz, CHLOROFORM-d) δ ppm1.23 (s, 6H) 1.76 (s, 6H) 2.11 (quin, J=6.99 Hz, 2H) 2.58 (s, 2H) 3.12(dt, J=16.15, 4.77 Hz, 1H) 3.27 (t, J=7.0 Hz, 4H) 3.36-3.45 (m, 1H) 3.90(s, 3H) 3.93-4.16 (m, 3H) 4.34-4.69 (m, 2H) 6.89 (d, J=8.69 Hz, 1H) 7.14(dd, J=11.71, 1.51 Hz, 1H) 7.25 (s, 1H) 7.32 (dd, J=8.69, 2.64 Hz, 1H)7.37-7.44 (m, 1H) 7.47-7.64 (m, 2H) 8.07 (d, J=2.64 Hz, 1H) 8.26 (s, 1H)8.52 (s, 1H).

Preparation of I-79 Example 79 Preparation of2-(8-Fluoro-2-{2-hydroxymethyl-3-[1-methyl-5-(5-oxetan-3-yl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazin-2-ylamino)-6-oxo-1,6-dihydro-pyridazin-3-yl]-phenyl}-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-methyl-propionitrile

6-chloro-2-methyl-4-(5-(oxetan-3-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-pyridazin-3(2H)-one(prepared as described in example 60, 65 mg, 194 μmol)bis(pinacolato)diboron (54.1 mg, 213 μmol) and potassium acetate (57.0mg, 581 μmol) were suspended in dioxane (9 ml). The reaction mixture wasdegassed under argon. X-PHOS (13.8 mg, 29.0 μmol) and palladium(II)acetate (2.17 mg, 9.68 μmol) were added and the reaction mixture wasstirred at 100° C. (external temperature) for 45 min under an argonatmosphere. LCMS (taken in methanol) showed some conversion to boronicacid (M+1=347) and some of the undesired2-methyl-4-(5-oxetan-3-yl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazin-2-ylamino)-2H-pyridazin-3-one.Heating was turned down to 80° C. The flask was raised out of theheating bath, but continued stirring.2-(2-(3-bromo-2-formylphenyl)-8-fluoro-1-oxo-1,2-dihydroisoquinolin-6-yl)-2-methylpropanenitrile(prepared as describe in example 15, 80 mg, 194 μmol) in 2 mL dioxanesand potassium carbonate (80.3 mg, 581 μmol) were added, followed by 1 mLH₂O. Tricyclohexylphosphine (5.43 mg, 19.4 μmol) andbis(dibenzylideneacetone)-palladium (0) (5.57 mg, 9.68 μmol) were added.The reaction mixture was heated with vigorous stirring at 80° C. for 1.5h. The crude reaction was poured onto H₂O and EtOAc and extracted 3times with EtOAc and 1 time with DCM. The combined organic extracts werewashed with brine and dried over MgSO₄. The crude material was purifiedby flash chromatography (silica gel, 24 g, 1% to 5% MeOH in DCM) toafford approx. 90 mg the intermediate2-(8-fluoro-2-(2-formyl-3-(1-methyl-5-(5-(oxetan-3-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)-1-oxo-1,2-dihydroisoquinolin-6-yl)-2-methylpropanenitrile.In a 25 mL round-bottomed flask,2-(8-fluoro-2-(2-formyl-3-(1-methyl-5-(5-(oxetan-3-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)-1-oxo-1,2-dihydroisoquinolin-6-yl)-2-methylpropanenitrile(90 mg, 142 μmol) was combined with dry CH₂Cl₂ (2 ml) and dry MeOH (0.5mL) to give a light yellow solution. The solution was cooled to 0° C.Sodium borohydride (9.66 mg, 255 μmol) was added. The reaction mixturewas stirred at 0° C. for 40 min. Complete by LCMS. Quenched with sat'dNH₄Cl. The reaction mixture was poured into 25 mL H₂O and extracted withDCM (2×50 mL). The organic layers were dried over Na₂SO₄ andconcentrated in vacuo. The crude material was purified by flashchromatography (silica gel, 24 g, 0% to 3% MeOH). Pure fractions wereconcentrated to give a glass, which was dissolved in 1 mL DCM andprecipitated with 20 mL ether to afford the desired product (18 mg) as awhite solid. (M+H)⁺=637 m/e. ¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.81(s, 6H) 2.90 (t, J=5.48 Hz, 2H) 3.55-3.71 (m, 2H) 3.77-3.86 (m, 1H) 3.89(s, 3 H) 4.17 (t, J=5.48 Hz, 2H) 4.26-4.42 (m, 2H) 4.66-4.87 (m, 4H)5.83 (s, 1H) 6.62 (dd, J=7.55, 1.89 Hz, 1H) 7.22 (dd, J=12.28, 1.70 Hz,1H) 7.34 (d, J=7.18 Hz, 1H) 7.41 (dd, J=7.74, 1.32 Hz, 1H) 7.50-7.61 (m,2H) 7.63-7.72 (m, 1H) 7.85 (s, 1H) 7.95 (s, 1H).

Preparation of I-80 Example 80 Preparation of6-tert-Butyl-8-fluoro-2-{2-hydroxymethyl-3-[1-methyl-5-(1′-oxetan-3-yl-1′,2′,3′,4′,5′,6′-hexahydro-[3,4]bipyridinyl-6-ylamino)-6-oxo-1,6-dihydro-pyridazin-3-yl]-phenyl}-2H-phthalazin-1-one

Step 1. To a solution of6-chloro-2-methyl-4-(5-(piperidin-4-yl)pyridin-2-ylamino)pyridazin-3(2H)-one(639 mg, 2.00 mmol, Eq: 1.00) and oxetan-3-one (288 mg, 4.00 mmol, Eq:2.0) in THF (10 ml) was added acetic acid (360 mg, 343 μl, 5.99 mmol,Eq: 3.0). The reaction mixture stirred under N₂, at 55° C. for 1 h. Thensodium triacetoxyborohydride (847 mg, 4.00 mmol, Eq: 2.0) was added andthe mixture was stirred at 65° C. for 2 h. The reaction mixture wascooled to room temperature and concentrated in vacuo. The residue waspartitioned between DCM and saturated NaHCO₃. The layers were separatedand the organic layer was washed with water. The organic layer was thendried over Na₂SO₄ and concentrated in vacuo. The crude material waspurified by flash chromatography (silica gel, 24 g, 0% to 40% (60:10:1DCM:MeOH:NH₄OH)/DCM) gradient) to give6-chloro-2-methyl-4-(1′-oxetan-3-yl-1′,2′,3′,4′,5′,6′-hexahydro-[3,4]bipyridinyl-6-ylamino)-2H-pyridazin-3-one(453 mg, 60%). LC/MS-ESI observed [M+H]⁺ 376. 1H NMR in CDCl₃ isconsistent with desired product.

Step 2. In a 50 mL test tube,6-chloro-2-methyl-4-(5-(1-(oxetan-3-yl)piperidin-4-yl)pyridin-2-ylamino)pyridazin-3(2H)-one(120 mg, 319 μmol) and2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate (271 mg, 383 μmol) were combined with BuOH (4 ml) to give aorange solution. 1 mL of water was added. Purged with argon. X-PHOS(15.2 mg, 31.9 μmol) and potassium phosphate tribasic (136 mg, 639 μmol)were added. Argon was bubbled through for 5 min.bis(Dibenzylideneacetone)-palladium (0) (9.18 mg, 16.0 μmol) was addedand the reaction mixture was placed under an argon atmosphere and waswarmed in a oil bath at 110° C. for 1.5 hours. No6-chloro-2-methyl-4-(5-(1-(oxetan-3-yl)piperidin-4-yl)pyridin-2-ylamino)pyridazin-3(2H)-oneremained by LCMS. Two main products were observed by LCMS, acetylatedand deacetylated product. The reaction mixture was allowed to cool to RTovernight and the concentrated to a small volume. The reaction mixturewas poured into 75 mL H₂O and extracted with EtOAc (3×75 mL). Theorganic layers were dried over Na₂SO₄ and concentrated in vacuo. Thecrude material was purified by flash chromatography (silica gel, 24 g,1% to 6% MeOH in DCM). Pure acetylated and deacetylated products andmixed fractions were combined and conc. to afford 162 mg of the mixture.This mixture of2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(1-methyl-5-(5-(1-(oxetan-3-yl)piperidin-4-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridazin-3-yl)benzylacetate (162 mg, 229 μmol, Eq: 1.00) and6-tert-butyl-8-fluoro-2-(2-(hydroxymethyl)-3-(1-methyl-5-(5-(1-(oxetan-3-yl)piperidin-4-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)phthalazin-1(2H)-one(152 mg, 229 μmol) was dissolved in 8 mL THF. 2 mL of 1N NaOH was added.The reaction was warmed at 50° C. for 6 hrs and then at 60° C. for 18 h.The reaction mixture was poured into 100 mL H₂O and extracted with EtOAc(2×75 mL) and DCM (1×75 ml). The combined organic extracts were washedwith brine, dried over MgSO₄ and concentrated in vacuo. The crudematerial was purified by flash chromatography (silica gel, 24 g, 0% to4% MeOH in DCM) and then by preparative tlc (3% MeOH in DCM eluent) toafford the desired product (78 mg) as a white solid. (M+H)⁺=666 m/e. ¹HNMR (300 MHz, CHLOROFORM-d) δ ppm 1.43 (s, 9H) 1.58 (br. s., 1H)1.72-2.06 (m, 3H) 2.89 (br. s., 1H) 3.75-4.09 (m, 4H) 4.43 (d, J=6.80Hz, 2H) 4.69 (d, J=6.42 Hz, 3H) 6.92 (d, J=8.31 Hz, 1H) 7.42-7.62 (m,5H) 7.63-7.71 (m, 1H) 8.17-8.35 (m, 3H) 8.61 (s, 1H)

Preparation of I-81 Example 81 Preparation of6-tert-Butyl-8-fluoro-2-{2-hydroxymethyl-3-[1-methyl-5-(1′-oxetan-3-yl-1′,2′,3′,4′,5′,6′-hexahydro-[3,4]bipyridinyl-6-ylamino)-6-oxo-1,6-dihydro-pyridazin-3-yl]-phenyl}-2H-phthalazin-1-one

Preparation by a similar procedure to Example 79, except substituting6-chloro-2-methyl-4-(1′-oxetan-3-yl-1′,2′,3′,4′,5′,6′-hexahydro-[3,4]bipyridinyl-6-ylamino)-2H-pyridazin-3-onefor6-chloro-2-methyl-4-(5-(oxetan-3-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-pyridazin-3(2H)-one,afforded the desired product as a white powder (173 mg).

(M+H)⁺=676 m/e. ¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.43-2.10 (m andoverlapping singlet, 14H) 2.54 (d, J=7.18 Hz, 1H) 2.91 (d, J=9.44 Hz,2H) 3.55 (br. s., 1H) 3.91 (s, 3H) 4.01 (dd, J=10.20, 4.15 Hz, 1H)4.20-4.50 (m, 2H) 4.69 (d and m, J=6.42 Hz, 3 H) 6.62 (dd, J=7.36, 2.08Hz, 1H) 6.92 (d, J=8.69 Hz, 1H) 7.22 (dd, J=12.46, 1.89 Hz, 1H) 7.35 (d,J=7.55 Hz, 1H) 7.42 (dd, J=7.74, 1.32 Hz, 1H) 7.49-7.64 (m, 3H)7.65-7.74 (m, 1H) 8.17-8.33 (m, 2H) 8.63 (s, 1H).

Preparation of I-82 Example 82 Preparation of6-tert-Butyl-2-{3-[5-(5-ethyl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazin-2-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl]-2-hydroxymethyl-phenyl}-8-fluoro-2H-phthalazin-1-one

Preparation by a similar procedure to Example 59, except substitutingethylamine for methyl amine in step 5 afforded the desired product as awhite powder (196 mg). (M+H)⁺=599 m/e. ¹H NMR (300 MHz, CHLOROFORM-d) δppm 1.21 (t, J=7.18 Hz, 3H) 1.43 (s, 9H) 2.67 (d, J=6.42 Hz, 2H) 2.99(br. s., 2H) 3.70 (br. s., 2H) 3.88 (s, 3H) 4.02 (t, J=6.99 Hz, 1H) 4.15(br. s., 2H) 4.40 (d, J=6.80 Hz, 2H) 5.83 (s, 1H) 7.41-7.59 (m, 4H)7.61-7.67 (m, 1H) 7.81 (s, 1H) 7.92 (s, 1H) 8.28 (d, J=2.64 Hz, 1H)

Preparation of I-83 Example 83 Preparation of2-(2-{3-[5-(5-Ethyl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazin-2-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl]-2-hydroxymethyl-phenyl}-8-fluoro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-methyl-propionitrile

Preparation by a similar procedure to Example 80, except substituting6-Chloro-4-(5-ethyl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazin-2-ylamino)-2-methyl-2H-pyridazin-3-onefor6-chloro-2-methyl-4-(5-(oxetan-3-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-pyridazin-3(2H)-one,afforded the desired product as a white powder (70 mg). (M+H)⁺=609 m/e.¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.13-1.29 (m, 3H) 1.57 (br. s., 2H)1.81 (s, 7H) 2.67 (br. s., 1H) 2.99 (br. s., 1H) 3.70 (br. s., 1H) 3.89(s, 3H) 4.02-4.21 (m, 3H) 4.22-4.47 (m, 2H) 5.81 (s, 1H) 6.61 (dd,J=7.36, 2.08 Hz, 1H) 7.21 (dd, J=12.09, 1.89 Hz, 1H) 7.35 (d, J=7.18 Hz,1H) 7.38-7.44 (m, 1H) 7.49-7.60 (m, 2H) 7.63-7.69 (m, 1H) 7.83 (s, 1H)7.94 (s, 1H).

Preparation of I-84 Example 84

6-tert-Butyl-2-[3-(5-{5-[(1S,4S)-1-(2,5-diaza-bicyclo[2.2.1]hept-2-yl)methyl]-pyridin-2-ylamino}-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl)-2-hydroxymethyl-phenyl]-8-fluoro-2H-phthalazin-1-onewas prepared using the general procedure described in Example 41,substituting (1S,4S)-tert-butyl2,5-diazabicyclo[2.2.1]heptane-2-carboxylate for 1-methylpiperazine. Inthe penultimate step of the synthesis for this compound, 1M NaOH wasused to remove the acetate protecting group rather than potassiumcarbonate, using THF as the solvent and heating at 60° C. for two hours,then stirring at room temperature overnight. The BOC protecting groupwas removed with 1,1,1,3,3,3-hexafluoro-2-propanol using the alcohol asthe solvent and heating at 140° C. for 30 minutes in a microwavereactor, then another 45 minutes at 150° C. After purification bychromatography using a gradient of 5% to 25% methanol in DCM, 50 mg ofproduct was obtained as an off-white powder. ¹H NMR (300 MHz, DMSO-d₆) δppm 9.39 (s, 1 H) 8.49-8.56 (m, 2H) 8.19-8.50 (m, 1H) 7.88 (s, 1H)7.71-7.76 (m, 1H) 7.54-7.61 (m, 1H) 7.44-7.51 (m, 4H) 4.56 (t, J=5.7 Hz,1H) 4.42 (br. s., 2H) 3.91 (s, 1H) 3.77 (s, 3H) 3.52-3.64 (m, 4H) 3.06(d, J=10.2 Hz, 1H) 2.71 (d, J=9.4 Hz, 2H) 2.38 (d, J=9.1 Hz, 1H) 1.72(d, J=10.2 Hz, 1H) 1.44 (d, J=7.6 Hz, 1H) 1.38 (s, 9H). MS: (M+H)⁺=637.MP>250° C.

Preparation of I-85 Example 85

Preparation by a similar procedure to Example 41, except substituting4-methyl-piperidin-4-ol for 1-methylpiperazine in step 1, afforded6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{5-[5-(4-hydroxy-4-methyl-piperidin-1-ylmethyl)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one(83 mg) as a white solid.

(M+H)⁺=654 m/e. ¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.26 (s, 3H) 1.43(s, 9H) 1.60 (d, J=13.97 Hz, 4H) 3.91 (s and overlapping multiplet, 4H)4.43 (d, J=7.18 Hz, 2H) 6.94 (d, J=8.31 Hz, 1H) 7.42-7.71 (m, 5H)8.23-8.34 (m, 3H) 8.65 (s, 1H)

Preparation of I-86 Example 86

Preparation by a similar procedure to Example 56, except substituting4-(6-nitro-pyridin-3-yl)-piperazine-1-carboxylic acid ethyl ester for1-methyl-4-(6-nitropyridin-3-yl)piperazine in step 1, afforded4-(6-{6-[3-(6-tert-Butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-2-methyl-3-oxo-2,3-dihydro-pyridazin-4-ylamino}-pyridin-3-yl)-piperazine-1-carboxylicacid ethyl ester (43 mg) as a yellow solid. (M+H)⁺=654 m/e. ¹H NMR (400MHz, CHLOROFORM-d) δ ppm 1.22 (t, J=7.15 Hz, 3H) 1.36 (s, 9H) 3.10 (br.s., 4H) 3.66 (br. s., 3H) 3.83 (s, 3H) 4.11 (q, J=7.11 Hz, 2H) 4.29-4.30(m, 1H) 4.35 (s, 2H) 7.03 (d, J=8.28 Hz, 1H) 7.34-7.64 (m, 6H) 8.00 (br.s., 1H) 8.22 (d, J=2.51 Hz, 1H) 8.36 (s, 1H).

Preparation of I-87

Preparation of8-Fluoro-6-(2-fluoro-1,1-dimethyl-ethyl)-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-isoquinolin-1-oneStep 1. Preparation of2-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-6-yl)-2-methylpropanal

A solution of2-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-6-yl)-2-methylpropanenitrile(1.77 g, 3.34 mmol) was prepared in THF/Toluene in an oven dried flask.The flask was cooled to −78° C. under a N₂ atmosphere. To this was addeda DiBAL-H (14 mL of 1M in hexanes, 14 mmol) via syringe over about 10minutes. The reaction mixture was stirred for 60 min at −78° C. and thenwarmed to 0° C. and stirred for 1 hour. To this resultant solution wasadded 50 ml of 3 N HCl (aq) and 50 ml of EtOAc. The mixture was shakenand the EtOAc phase was collected and washed with 25 ml of brine. Theaqueous phase was back extracted (2×40 ml EtOAc). The organic layer wasdried (MgSO₄), filtered and conc. in vacuo. Only 344 mg of crude productwas obtained. Product was crystallized from hot DCM/Hexane. Product wascollected by filtration to afford 280 mg of a white crystalline product.(M+H)⁺=234 m/e.

Step 2. Preparation of8-fluoro-6-(1-hydroxy-2-methylpropan-2-yl)isoquinolin-1(2H)-one

2-(8-Fluoro-1-oxo-1,2-dihydroisoquinolin-6-yl)-2-methylpropanal (137 mg,587 μmol) was dissolved in MeOH and cooled in an ice bath. To theresulting solution was added NaBH₄ (33 mg, 881 μmol) in one portion. Thereaction mixture was stirred vigorously for 5 minutes before removingthe cooling bath and stirring for 30 minutes. To the reaction mixturewas added about 40 ml of 10% HCl and 40 ml EtOAc. The mixture was shakenand the EtOAc phase collected. The organic phase was washed with anequal volume of water. The aqueous phase was back extracted with 2×30 mlEtOAc. The combined organic phase was dried (MgSO₄), filtered andconcentrated in vacuo to afford 109 mg of a off-white powder. (M+H)⁺=236m/e.

Step 3. Preparation of8-fluoro-6-(1-fluoro-2-methylpropan-2-yl)isoquinolin-1(2H)-one

8-fluoro-6-(1-hydroxy-2-methylpropan-2-yl)isoquinolin-1(2H)-one (114 mg,485 μmol) was dissolved in DCM (dry) and cooled to −78° C. under argon.To this solution was added the diethylaminosulfur trifluoride (90 μl,678 μmol) and the reaction was stirred for about 10 min before removalof the cooling bath. The reaction was warmed to ambient and stirred atthis temperature for 2 hrs. To the reaction mixture was added 25 mlwater and 20 ml DCM. The mixture was shaken and the organics collected.The organics were washed with 25 ml brine. The aqueous phase wasextracted (2×20 ml DCM). The combined organics were dried (MgSO₄),filtered and concentrated in vacuo. The crude product was purified bypreparative tlc (2 plates, eluted with 4.5% MeOH/DCM) to afford 92 mg ofthe desired product as an off-white powder.

(M+H)⁺=238 m/e.

Step 4. Preparation of2-Chloro-6-[8-fluoro-6-(2-fluoro-1,1-dimethyl-ethyl)-1-oxo-1H-isoquino-lin-2-yl]-benzaldehyde-6,8-difluoro-3,4-dihydro-2H-isoquinolin-1-one

In a 250 mL round-bottomed flask,8-fluoro-6-(1-fluoro-2-methylpropan-2-yl)isoquinolin-1(2H)-one (92 mg,388 μmol), 2-bromo-6-chlorobenzaldehyde (136 mg, 620 mmol) and potassiumcarbonate (107 mg, 776 μmol) were combined with DMSO (1.23 ml) to give ayellow suspension. The mixture was degassed with argon for 5 min.Copper(I) iodide (73.9 mg, 13.1 μl, 388 μmol) was added and theresulting mixture was placed in a oil bath at 110° C. The reactionmixture was heated to 110° C. and stirred for 1.5 h. Reaction was notcomplete by LCMS. More 2-bromo-6-chlorobenzaldehyde (70 mg) was added.The reaction mixture was heated to 110° C. and stirred for 3 h, thenallowed to cool to ambient. The crude reaction mixture was filteredthrough a plug of celite and washed through with EtOAc. The combinedfiltrate and washes were added to a separatory funnel with 25 ml of 1:1diluted sat NH₄Cl/water. The organic phase was collected and washed withan equal volume of brine. The aqueous phase was extracted (2×20 mlEtOAc). The combined organic phase was dried (MgSO₄), filtered andconcentrated in vacuo. The crude product was purified by preparativetlc: 2 plates; eluted with 2% MeOH/DCM to afford the desired product(106 mg) as a light yellow semi-solid. (M+H)⁺=376 m/e.

Example 87

Preparation by a procedure similar to Example 15 (steps 11-12), exceptsubstituting2-chloro-6-[8-fluoro-6-(2-fluoro-1,1-dimethyl-ethyl)-1-oxo-1H-isoquinolin-2-yl]-benzaldehydefor6-chloro-2-methyl-4-(5-morpholine-4-carbonyl)pyridine-2-ylamino)pyridazin-3(2H)-onein step 11, afforded8-fluoro-6-(2-fluoro-1,1-dimethyl-ethyl)-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-isoquinolin-1-one(43 mg) as a yellow solid. (M+H)⁺=657 m/e. ¹H NMR (300 MHz,CHLOROFORM-d) δ ppm 1.36 (s, 3H) 1.43 (s, 3H) 2.92-3.10 (m, 2H)3.56-3.80 (m, 8H) 3.91 (s, 4H) 4.38 (d, J=4.15 Hz, 2H) 6.57 (dd, J=7.55,1.89 Hz, 1H) 6.97-7.14 (m, 2H) 7.25 (dd, J=10.39, 2.83 Hz, 2H) 7.41 (dd,J=7.74, 1.32 Hz, 1H) 7.52-7.70 (m, 2H) 7.77 (dd, J=8.31, 2.27 Hz, 1H)8.38-8.53 (m, 2H) 8.70 (s, 1H).

Preparation of I-88 Example 88 Step 1. Preparation of6-Chloro-3-methoxy-4-trimethylsilanyl-pyridazine

In a 2-necked round bottom flask under argon placed 4.0476 g ofdistilled diisopropylamine and 60 mL of tetrahydrofuran (Aldrich,anhydrous, no stabilizer). The mixture was cooled to −78° C., then ca 20mL of 2.0 M butyl lithium in cyclohexane was added. The mixture was setin an ice bath for 20 minutes, then cooled to −78° C. and a solution of2.8912 g of 3-chloro-6-methoxy-pyridazine and 3.05 mL of chlorotrimethylsilane in 12 mL of tetrahydrofuran was added over 15 minutes. Themixture was stirred for 2 hours (a deep red color formed, then faded toyellow), then quenched by the addition of 10 mL of saturated sodiumdihydrogen phosphate solution. The mixture was taken up in 350 mL ofethyl acetate, washed 1×75 mL brine, dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure.

4.4056 g amber oil which was purified by chromatography on silica gel(silicycle 80 g column, 3.4×19.2 cm (174 mL volume), sample applied indichloromethane, eluted with dichloromethane-ethyl acetate (199:1) thedesired product (3.4 g).

Step 2. Preparation of6-chloro-2-methyl-4-trimethylsilanyl-2H-pyridazin-3-one and6-iodo-2-methyl-4-trimethylsilanyl-2H-pyridazin-3-one

In round bottom flask was placed 1.6068 g6-chloro-3-methoxy-4-trimethylsilanyl-pyridazine and 40 mL of chloroform(Aldrich, anhydrous, amylene inhibitor). The mixture was vacuum flushed3× argon, then was added 3.33 mL of iodotrimethyl silane in 5 mL ofchloroform (reaction turned amber). The flask was set in a bath at 60°C. and stirred. After 2 hours, the mixture was cooled and the reactionmixture was taken up in 450 mL of dichloromethane, washed 1×200 mL brinecontaining 5 g sodium thiosulfate and 3.6 g of K₂HPO₄, dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure. The crude product was purified by chromatographyon (silicagel, Silicycle 40 (2.6×13.3 cm 71 mL vol), sample applied in solvent,eluting with dichloromethane-ethyl acetate (90:10) afforded 2.69 gyellow solid, which consisted of 4:3 mixture of6-chloro-4-trimethylsilanyl-2H-pyridazin-3-one and6-iodo-4-trimethylsilanyl-2H-pyridazin-3-one. This mixture was placed ina round bottom flask under argon. To this was added 5.48 g cesiumcarbonate and 15 mL of dimethylformamide. The mixture was cooled in anice bath and 2.38 g iodomethane was added over 60 seconds. The coolingbath was removed and the mixture stirred at room temperature. After 90minutes, the mixture was taken up in 400 mL dichloromethane, washed 3×75mL water, 1×75 mL brine, dried over anhydrous sodium sulfate, filteredand concentrated under reduced pressure. The crude product was purifiedon silica gel (Silicycle 40 (2.6×13.3 cm 71 mL vol), sample applied insolvent, eluting with dichloromethane-ethyl acetate (98:2)) to afford2.53 g of an off white solid as a 6:4 mixture of6-chloro-2-methyl-4-trimethylsilanyl-2H-pyridazin-3-one and6-iodo-2-methyl-4-trimethylsilanyl-2H-pyridazin-3-one.

Step 3. Preparation of Acetic acid2-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-6-(1-methyl-6-oxo-5-trimethylsilanyl-1,6-dihydro-pyridazin-3-yl)-benzylester

In round bottom flask was placed 3.21 g acetic acid2-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzylester, 2.06 g sodium carbonate, 0.68 g bistriphenylphosphine palladiumdichloride, and 1.99 g a 6:4 mixture of6-chloro-2-methyl-4-trimethylsilanyl-2H-pyridazin-3-one and6-iodo-2-methyl-4-trimethylsilanyl-2H-pyridazin-3-one followed by 130 mLof dioxane (EM DriSolv)-water (10:1). The mixture was vacuum flushed 5×argon, then set in a bath at 95° C. and stirred (mechanical). After 5.5hours, the mixture was cooled, taken up in 350 mL of ethyl acetate andwashed 1×75 mL of brine. The ethyl acetate layer was dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure. The crude product was purified by chromatography on silica gel(Silicycle 120 g, 3.5×21.5 cm, 207 vol), applied in dichloromethaneeluting with CH₂Cl₂-ethyl acetate (80:20), followed by chromatography onsilica gel (Silicycle 120 g, 3.5×21.5 cm, 207 vol), applied indichloromethane, eluting with dichloromethane-ethyl acetate (80:20)afforded 2.5418 g (71%) of product as a foam.

Step 4. Preparation of acetic acid acetic acid2-(5-bromo-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl)-6-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-benzylester

In round bottom flask with reflux condenser was placed 2.54 g aceticacid2-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-6-(1-methyl-6-oxo-5-trimethylsilanyl-1,6-dihydro-pyridazin-3-yl)-benzylester, 5.51 g potassium bromide, 4.55 g potassium acetate, followed byca 18.4908 g bromine. The mixture warmed on addition of the bromine. Themixture was stirred for 2 minutes at room temperature, then set in abath at 55° C. and stirred. A stopper was placed lightly in the top ofthe reflux condenser to contain the bromine vapors. After 70 minutes,the mixture was cooled to room temperature, excess bromine removed undera stream of nitrogen. The mixture was taken up in 500 mL ofdichloromethane, washed 1×150 mL brine, containing 12 g sodium bisulfitewith some resultant exotherm, dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure. Purification bychromatography on silica gel (Silicycle 120 g, 3.5×21.5 cm, 207 vol),applied in dichloromethane, eluting with dichloromethane-ethyl acetate(80:20), followed by chromatography on silica gel (Silicycle 120 g,3.5×21.5 cm, 207 vol), applied in dichloromethane, eluting withdichloromethane-ethyl acetate (80:20) to afford the desired product(1.91 g) as an off white solid.

Step 5. Preparation of acetic acid6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5((1S,4S)-5-methyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-pyrazin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one

5-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyrazin-2-amine(prepared by a similar procedure4-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-ylamine in example34, 50 mg, 292 μmol),2-(5-bromo-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-6-(6-tert-butyl-8-fluoro-1-oxophthala-zin-2(1H)-yl)benzylacetate (170 mg, 307 μmol), cesium carbonate (286 mg, 877 μmol),xantphos (25 mg, 44 μmol), tris(dibenzylideneacetone)dipalladium (0) (20mg, 22 mmol) and dioxane (3 mL) were combined in a microwave vial,degassed with argon and heated at 100° C. for 18 h. The crude reactionmixture was filtered through celite, concentrated and purified bychromatography using a gradient of 0% to 25% methanol in DCM. Theresulting residue, which was a mixture of acetylated and deacetylatedproduct, was dissolved in methanol. Potassium carbonate (61 mg, 441μmol) was added and the reaction was heated at 40° C. for 1 hr. Waterwas added dropwise and the resultant mixture was stirred at roomtemperature overnight. The solid was collected by filtration.Purification by preparative tlc in 10% methanol in DCM afforded thedesired product (17 mg) as a yellow powder. (M+H)⁺=638 m/e.

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.37 (s, 9H) 1.66-1.92 (m, 2H) 2.25 (s,3H) 2.78 (d, J=8.31 Hz, 1H) 3.41 (d, J=10.20 Hz, 2H) 3.75 (s, 3H)4.28-4.58 (m, 4H) 7.39-7.55 (m, 3H) 7.68-7.79 (m, 2H) 7.85 (d, J=1.51Hz, 1H) 8.05 (s, 1H) 8.35 (d, J=1.51 Hz, 1H) 8.49 (d, J=2.27 Hz, 1H)9.34 (s, 1H).

Preparation of I-89 Example 89

2-[8-Fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-((S)-1-methyl-pyrrolidin-3-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-1-oxo-1,2-dihydro-isoquinolin-6-yl]-2-methyl-propionitrilewas prepared using the general procedure described for compound I-15,but substituting6-chloro-2-methyl-4-[5-((R)-1-methyl-pyrrolidin-3-yl)-pyridin-2-ylamino]-2H-pyridazin-3-onefor6-chloro-2-methyl-4-(5-morpholine-4-carbonyl)pyridine-2-ylamino)pyrid-azin-3(2H)-onein step 11 to provide 32 mg of final product as a light yellow powder.

(M+H)⁺=620 m/e.

Preparation of I-90 Example 90 Preparation of6-tert-butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-6-oxo-5-[1′-(2,2,2-trifluoro-ethyl)-1′,2′,3′,4′,5′,6′-hexahydro-[3,4′]bipyridinyl-6-ylamino]-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one

To a solution of6-tert-butyl-8-fluoro-2-(2-(hydroxymethyl)-3-(1-methyl-6-oxo-5-(5-(piperidin-4-yl)pyridin-2-ylamino)-1,6-dihydropyridazin-3-yl)phenyl)phthalazin-1(2H)-one(10 mg, 16.4 μmol) in DMF (1 ml) was added potassium carbonate (6.8 mg,49.2 μmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (3.81 mg,2.36 μl, 16.4 μmol) at room temperature. The mixture was stirred for 8h. at the same temperature. EtOAc was added into the reaction mixture(10 mL) and the mixture was poured into water (10 mL). Organic layer wasseparated, washed with water (4×5 mL), dried (Na₂SO₄), and evaporatedunder vacuum. Crude product was purified by preparative tlc(CH₂Cl₂:MeOH:NH₄OH, 90:9.5:0.5) to give 8 mg of pure product (70%yield): m/z 692[M+H]⁺.

Assay Data Bruton's Tyrosine Kinase (Btk) Inhibition Assay

The assay is a capture of radioactive ³³P phosphorylated product throughfiltration. The interactions of Btk, biotinylated SH₂ peptide substrate(Src homology), and ATP lead to phosphorylation of the peptidesubstrate. Biotinylated product is bound streptavidin sepharose beads.All bound, radiolabeled products are detected by scintillation counter.

Plates assayed are 96-well polypropylene (Greiner) and 96-well 1.2 μmhydrophilic PVDF filter plates (Millipore). Concentrations reported hereare final assay concentrations: 10-100 μM compounds in DMSO (Burdick andJackson), 5-10 nM Btk enzyme (His-tagged, full-length), 30 μM peptidesubstrate (Biotin-Aca-AAAEEIYGEI-NH₂), 100 μM ATP (Sigma), 8 mMimidazole (Sigma, pH 7.2), 8 mM glycerol-2-phosphate (Sigma), 200 μMEGTA (Roche Diagnostics), 1 mM MnCl₂ (Sigma), 20 mM MgCl₂ (Sigma), 0.1mg/ml BSA (Sigma), 2 mM DTT (Sigma), 1 μCi ³³P ATP (Amersham), 20%streptavidin sepharose beads (Amersham), 50 mM EDTA (Gibco), 2 M NaCl(Gibco), 2 M NaCl w/1% phosphoric acid (Gibco), microscint-20 (PerkinElmer).

IC₅₀ determinations are calculated from 10 data points per compoundutilizing data pro-duced from a standard 96-well plate assay template.One control compound and seven unknown inhibitors were tested on eachplate and each plate was run twice. Typically, compounds were diluted inhalf-log starting at 100 μM and ending at 3 nM. The control compound wasstaurosporine. Background was counted in the absence of peptidesubstrate. Total activity was determined in the presence of peptidesubstrate. The following protocol was used to determine Btk inhibition.

1) Sample preparation: The test compounds were diluted at half-logincrements in assay buffer (imidazole, glycerol-2-phosphate, EGTA,MnCl₂, MgCl₂, BSA).2) Bead preparation

a.) rinse beads by centrifuging at 500 g

b.) reconstitute the beads with PBS and EDTA to produce a 20% beadslurry

3) Pre-incubate reaction mix without substrate (assay buffer, DTT, ATP,³³P ATP) and mix with substrate (assay buffer, DTT, ATP, ³³P ATP,peptide substrate) 30° C. for 15 min.4) To start assay, pre-incubate 10 μL Btk in enzyme buffer (imidazole,glycerol-2-phosphate, BSA) and 10 μL of test compounds for 10 min at RT.5) Add 30 μL reaction mixture without or with substrate to Btk andcompounds.6) Incubate 50 μL total assay mix for 30 min at 30° C.7) Transfer 40 μL of assay to 150 μL bead slurry in filter plate to stopreaction.8) Wash filter plate after 30 min, with following steps

a. 3×250 μL NaCl

b. 3×250 μL NaCl containing 1% phosphoric acid

c. 1×250 μL H₂O

9) Dry plate for 1 h at 65° C. or overnight at RT10) Add 50 μL microscint-20 and count ³³P cpm on scintillation counter.

-   -   Calculate percent activity from raw data in cpm

percent activity=(sample−bkg)/(total activity−bkg)×100

Calculate IC₅₀ from percent activity, using one-site dose responsesigmoidal model

y=A+((B−A)/(1+((x/C)^(D)))))

x=cmpd conc, y=% activity, A=min, B=max, C=IC₅₀, D=1 (hill slope)

Inhibition of B Cell Activation in Whole Blood Measured by CD69Expression

A procedure to test the ability of Btk inhibitors to suppress B cellreceptor-mediated activation of B cells in human blood is as follows:

Human whole blood (HWB) is obtained from healthy volunteers, with thefollowing restrictions: 24 hr drug-free, non-smokers. Blood is collectedby venipuncture into Vacutainer tubes anticoagulated with sodiumheparin. Test compounds are diluted to ten times the desired startingdrug concentration in PBS (20×), followed by three-fold serial dilutionsin 10% DMSO in PBS to produce a nine point dose-response curve. 5.5 μlof each compound dilution is added in duplicate to a 2 ml96-well Vbottom plate (Analytical Sales and Services, #59623-23); 5.5 μl of 10%DMSO in PBS is added to control and no-stimulus wells. HWB (100 μl) isadded to each well, and after mixing the plates are incubated at 37 C,5% CO₂, 100% humidity for 30 minutes. Goat F(ab′)2 anti-human IgM(Southern Biotech, #2022-14) (10 μl of a 500 m/ml solution, 50 μg/mlfinal concentration) is added to each well (except the no-stimuluswells) with mixing and the plates are incubated for an additional 20hours.

At the end of the 20 hour incubation, samples are incubated withflorescent-probe-labeled anti-bodies (15 μl PE Mouse anti-Human CD20, BDPharmingen, #555623, and/or 20 ul APC Mouse anti-Human CD69, BDPharmingen #555533) for 30 minutes, at 37 C, 5% CO₂, 100% humidity.Included are induced control, unstained and single stains forcompensation adjustments and initial voltage settings. Samples are thenlysed with 1 ml of 1X Pharmingen Lyse Buffer (BD Pharmingen #555899),and plates are centrifuged at 1800 rpm for 5 minutes. Supernatants areremoved via suction and the remaining pellets are lysed again withanother 1 ml of 1X Pharmingen Lyse Buffer, and plates are spun down asbefore. Supernatants are aspirated and remaining pellets are washed inFACs buffer (PBS+1% FBS). After a final spin, the supernantants areremoved and pellets are resuspended in 180 μl of FACs buffer. Samplesare transferred to a 96 well plate suitable to be run on the HTS 96 wellsystem on the BD LSR II flow cytometer.

Using appropriate excitation and emission wavelengths for thefluorophores used, data are acquired and percent positive cell valuesare obtained using Cell Quest Software. Results are initially analyzedby FACS analysis software (Flow Jo). The IC50 for test compounds isdefined as the concentration which decreases by 50% the percentage ofCD69-positive cells that are also CD20-positive after stimulation byanti-IgM (average of 8 control wells, after subtraction of the averageof 8 wells for the no-stimulus background). The IC50 values arecalculated using XLfit software version 3, equation 201.

Representative compound data for this assay are listed below in TableII.

TABLE II Human Whole Blood Compound (μM) I-1  0.019 I-2  0.014 I-3 0.045 I-4  0.122 I-5  0.025 I-6  0.031 I-7  0.02 I-8  0.02 I-10 0.019I-12 0.052 I-13 0.009 I-14 0.065 I-15 0.163 I-16 0.026 I-17 0.041 I-180.003 I-19 0.007 I-20 0.015 I-21 0.109 I-22 0.033 I-23 0.06 I-24 0.116I-26 0.152 I-27 0.089 I-28 0.006 I-29 0.015 I-30 0.004 I-31 0.032 I-320.023 I-33 0.002 I-34 0.125 I-35 0.074 I-37 0.084 I-38 0.012 I-39 0.021I-40 0.044 I-41 0.015 I-42 0.047 I-43 0.041 I-44 0.014 I-45 0.027 I-460.293 I-47 0.076 I-48 0.185 I-49 0.085 I-50 0.086 I-51 0.019 I-52 0.027I-53 0.039 I-54 0.104 I-55 0.041 I-56 0.017 I-58 0.002 I-59 0.005 I-600.004 I-61 0.074 I-62 0.144 I-63 0.189 I-64 0.066 I-65 0.062 I-66 0.023I-67 0.004 I-68 0.061 I-69 0.018 I-70 0.117 I-71 0.032 I-72 0.056 I-730.03 I-74 0.034 I-75 0.18 I-76 0.051 I-77 0.123 I-78 0.084 I-79 0.06I-80 0.041 I-81 0.123 I-82 0.017 I-83 0.07 I-84 0.242 I-85 0.294 I-860.408 I-87 0.455 I-88 0.203 I-89 0.485 I-90 0.34

Inhibition of B-Cell Activation—B Cell Flipr Assay in Ramos Cells

Inhibition of B-cell activation by compounds of the present invention isdemonstrated by determining the effect of the test compounds on anti-IgMstimulated B cell responses.

The B cell FLIPR assay is a cell based functional method of determiningthe effect of potential inhibitors of the intracellular calcium increasefrom stimulation by an anti-IgM antibody. Ramos cells (human Burkitt'slymphoma cell line. ATCC-No. CRL-1596) were cultivated in Growth Media(described below). One day prior to assay, Ramos cells were resuspendedin fresh growth media (same as above) and set at a concentration of0.5×10⁶/mL in tissue culture flasks. On day of assay, cells are countedand set at a concentration of 1×10⁶/mL1 in growth media supplementedwith 1 μM FLUO-3AM(TefLabs Cat-No. 0116, prepared in anhydrous DMSO and10% Pluronic acid) in a tissue culture flask, and incubated at 37° C.(4% CO₂) for one h. To remove extracellular dye, cells were collected bycentrifugation (5 min, 1000 rpm), resuspended in FLIPR buffer (describedbelow) at 1×10⁶ cells/mL and then dispensed into 96-well poly-D-lysinecoated black/clear plates (BD Cat-No. 356692) at 1×10⁵ cells per well.Test compounds were added at various concentrations ranging from 100 μMto 0.03 μM (7 concentrations, details below), and allowed to incubatewith cells for 30 min at RT. Ramos cell Ca²⁺ signaling was stimulated bythe addition of 10 μg/mL anti-IgM (Southern Biotech, Cat-No. 2020-01)and measured on a FLIPR (Molecular Devices, captures images of 96 wellplates using a CCD camera with an argon laser at 480 nM excitation).

Media/Buffers:

Growth Medium: RPMI 1640 medium with L-glutamine (Invitrogen, Cat-No.61870-010), 10% Fetal Bovine Serum (FBS, Summit Biotechnology Cat-No.FP-100-05); 1 mM Sodium Pyruvate (Invitrogen Cat. No. 11360-070).

FLIPR buffer: HBSS (Invitrogen, Cat-No. 141175-079), 2 mM CaCl₂ (SigmaCat-No. C-4901), HEPES (Invitrogen, Cat-No. 15630-080), 2.5 mMProbenecid (Sigma, Cat-No. P-8761), 0.1% BSA (Sigma, Cat-No.A-7906), 11mM Glucose (Sigma, Cat-No.G-7528)

Compound Dilution Details:

In order to achieve the highest final assay concentration of 100 μM, 24μL of 10 mM compound stock solution (made in DMSO) is added directly to576 μL of FLIPR buffer. The test compounds are diluted in FLIPR Buffer(using Biomek 2000 robotic pipettor) resulting in the following dilutionscheme: vehicle, 1.00×10⁻⁴ M, 1.00×10⁻⁵, 3.16×10⁻⁶, 1.00×10⁻⁶,3.16×10⁻⁷, 1.00×10⁻⁷, 3.16×10⁻⁸.

Assay and Analysis:

Intracellular increases in calcium were reported using a max-minstatistic (subtracting the resting baseline from the peak caused byaddition of the stimulatory antibody using a Molecular Devices FLIPRcontrol and statistic exporting software. The IC₅₀ was determined usinga non-linear curve fit (GraphPad Prism software).

Mouse Collagen-Induced Arthritis (mCIA)

On day 0 mice are injected at the base of the tail or several spots onthe back with an emulsion of Type II Collagen (i.d.) in CompleteFreund's adjuvant (CFA). Following collagen immunization, animals willdevelop arthritis at around 21 to 35 days. The onset of arthritis issynchronized (boosted) by systemic administration of collagen inIncomplete Freund's adjuvant (IFA; i.d.) at day 21. Animals are examineddaily after day 20 for any onset of mild arthritis (score of 1 or 2; seescore description below) which is the signal to boost. Following boost,mice are scored and dosed with candidate therapeutic agents for theprescribed time (typically 2-3 weeks) and dosing frequency, daily (QD)or twice-daily (BID).

Rat Collagen-Induced Arthritis (rCIA)

On day 0, rats are injected with an emulsion of Bovine Type II Collagenin Incomplete Freund's adjuvant (IFA) is injected intradermally (i.d.)on several locations on the back. A booster injection of collagenemulsion is given around day 7, (i.d.) at the base of the tail oralternative sites on the back. Arthritis is generally observed 12-14days after the initial collagen injection. Animals may be evaluated forthe development of arthritis as described below (Evaluation ofarthritis) from day 14 onwards. Animals are dosed with candidatetherapeutic agents in a preventive fashion starting at the time ofsecondary challenge and for the prescribed time (typically 2-3 weeks)and dosing frequency, daily (QD) or twice-daily (BID).

Evaluation of Arthritis:

In both models, developing inflammation of the paws and limb joints isquantified using a scoring system that involves the assessment of the 4paws following the criteria described below:

Scoring: 1=swelling and/or redness of paw or one digit.

-   -   2=swelling in two or more joints.    -   3=gross swelling of the paw with more than two joints involved.    -   4=severe arthritis of the entire paw and digits.

Evaluations are made on day 0 for baseline measurement and startingagain at the first signs or swelling for up to three times per weekuntil the end of the experiment. The arthritic index for each mouse isobtained by adding the four scores of the individual paws, giving amaximum score of 16 per animal.

Rat In Vivo Asthma Model

Male Brown-Norway rats are sensitized i.p. with 100 μg of OA (ovalbumin)in 0.2 ml alum once every week for three weeks (day 0, 7, and 14). Onday 21 (one week following last sensitization), the rats are dosed q.d.with either vehicle or compound formulation subcutaneously 0.5 hourbefore OA aerosol challenge (1% OA for 45 minutes) and terminated 4 or24 hours after challenge. At time of sacrifice, serum and plasma arecollected from all animals for serology and PK, respectively. A trachealcannula is inserted and the lungs are lavaged 3× with PBS. The BAL fluidis analyzed for total leukocyte number and differential leukocytecounts. Total leukocyte number in an aliquot of the cells (20-100 μl) isdetermined by Coulter Counter. For differential leukocyte counts, 50-200μl of the sample is centrifuged in a Cytospin and the slide stained withDiff-Quik. The proportions of monocytes, eosinophils, neutrophils andlymphocytes are counted under light microscopy using standardmorphological criteria and expressed as a percentage. Representativeinhibitors of Btk show decreased total leucocyte count in the BAL of OAsensitized and challenged rats as compared to control levels.

The foregoing invention has been described in some detail by way ofillustration and example, for purposes of clarity and understanding. Itwill be obvious to one of skill in the art that changes andmodifications may be practiced within the scope of the appended claims.Therefore, it is to be understood that the above description is intendedto be illustrative and not restrictive. The scope of the inventionshould, therefore, be determined not with reference to the abovedescription, but should instead be determined with reference to thefollowing appended claims, along with the full scope of equivalents towhich such claims are entitled.

All patents, patent applications and publications cited in thisapplication are hereby incorporated by reference in their entirety forall purposes to the same extent as if each individual patent, patentapplication or publication were so individually denoted.

What is claimed is:
 1. A compound of Formula I,

wherein:

is either a single or double bond; X is either CH, CH₂, or N; R is H,-R¹, -R¹-R²-R³, -R¹-R³, or -R²-R³; R¹ is aryl, heteroaryl, bicyclicheteroaryl, cycloalkyl, or heterocycloalkyl, each of which is optionallysubstituted with one or more lower alkyl, hydroxy, hydroxy lower alkyl,lower alkoxy, halo, nitro, amino, amido, cyano, oxo, or lower haloalkyl;R² is —C(═O), —C(═O)O, —C(═O)NR^(2′), —NHC(═O)O, —C(R^(2′))₂, —O, —S,—C(═NH)NR^(2′), or —S(═O)₂; each R^(2′) is independently H or loweralkyl; R³ is H or R⁴; R⁴ is lower alkyl, lower haloalkyl, lower alkoxy,amino, lower alkyl amino, cycloalkyl amino, lower dialkyl amino, aryl,arylalkyl, alkylaryl, heteroaryl, alkyl heteroaryl, heteroaryl alkyl,cycloalkyl, alkyl cycloalkyl, cycloalkyl alkyl, heterocycloalkyl, alkylheterocycloalkyl, heterocycloalkyl alkyl, bicyclic cycloalkyl, bicyclicheterocycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, or bicyclicspiroheterocycloalkyl, each of which is optionally substituted with oneor more lower alkyl, halo, lower alkyl amino, lower dialkyl amino,hydroxy, hydroxy lower alkyl, lower alkoxy, lower alkanoyl, halo, nitro,amino, amido, acyl, cyano, oxo, sulfonyl, lower alkyl sulfonyl,guanidino, hydroxylamino, carboxy, carbamoyl, carbamate, halo loweralkoxy, heterocycloalkyl, or halo lower alkyl, wherein two lower alkylgroups may together form a ring; Y⁴ is Y^(4a), Y^(4b), Y^(4c), orY^(4d); Y^(4a) is H or halogen; Y^(4b) is lower alkyl, optionallysubstituted with one or more substituents selected from the groupconsisting of lower haloalkyl, halogen, hydroxy, amino, cyano, and loweralkoxy; Y^(4c) is lower cycloalkyl, optionally substituted with one ormore substituents selected from the group consisting of lower alkyl,lower haloalkyl, halogen, hydroxy, amino, cyano, and lower alkoxy; andY^(4d) is amino, optionally substituted with one or more lower alkyl,alkoxy lower alkyl, or hydroxy lower alkyl; or a pharmaceuticallyacceptable salt thereof.
 2. The compound of claim 1, wherein

is a double bond and X is N.
 3. The compound of claim 1, wherein

is a single bond and X is CH₂.
 4. The compound of claim 2, wherein R is-R¹-R²-R³; R¹ is pyridyl; R² is —S(═O)₂, R³ is R⁴; and R⁴ is loweralkyl.
 5. The compound of claim 2, wherein R is -R¹-R²-R³; R¹ ispyridyl; R² is —C(CH₃)₂; R³ is R⁴; and R⁴ is lower alkyl amino, lowerdialkyl amino, or heterocycloalkyl optionally substituted with one ormore lower alkyl.
 6. The compound of claim 2, wherein R is -R¹-R²-R³; R¹is phenyl or pyridyl; R² is —C(═O); R³ is R⁴; and R⁴ is morpholine orpiperazine, optionally substituted with one or more lower alkyl.
 7. Thecompound of claim 2, wherein Y⁴ is tert-butyl.
 8. The compound of claim3, wherein

is a double bond, X is CH, and Y⁴ is

wherein, Y⁵ and Y⁶ are independently H, lower alkyl, or lower haloalkyl.9. The compound of claim 2, wherein Y⁴ is

wherein, Y⁵ is H, halogen, lower alkyl or lower haloalkyl.
 10. Thecompound of claim 2, wherein Y⁴ is

wherein, Y⁵ and Y⁶ are independently H or lower alkyl.
 11. The compoundof claim 7, wherein R is -R¹-R³; R¹ is pyridyl or pyrazolopyrazine; R³is R⁴; and R⁴ is optionally substituted lower alkyl, heterocycloalkyl,or alkyl heterocycloalkyl.
 12. The compound of claim 7, wherein R is-R¹-R²-R³; R¹ is pyridyl; R² is —C(CH₃)₂; R³ is R⁴; and R⁴ is loweralkyl amino, lower dialkyl amino, or heterocycloalkyl optionallysubstituted with one or more lower alkyl.
 13. The compound of claim 7,wherein R is -R¹-R²-R³; R¹ is pyridyl; R² is —C(═O); R³ is R⁴; and R⁴ isoptionally substituted heterocycloalkyl or bicyclicspiroheterocycloalkyl.
 14. The compound of claim 13, wherein R⁴ isoptionally substituted morpholine or piperazine.
 15. The compound ofclaim 1 selected from the group consisting of:6-tert-Butyl-2-(3-{5-[5-(1-ethylamino-1-methyl-ethyl)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-2-hydroxymethyl-phenyl)-8-fluoro-2H-phthalazin-1-one;6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one;6-tert-Butyl-8-fluoro-2-{2-hydroxymethyl-3-[5-(5-methanesulfonyl-pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl]-phenyl}-2H-phthalazin-1-one;6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{5-[5-(3-methoxy-azetidin-1-ylmethyl)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one;6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(8-methyl-3,8-diaza-bicyclo[3.2.1]oct-3-ylmethyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one;6-tert-Butyl-2-(3-{5-[5-(2-dimethylamino-1,1-dimethyl-ethoxy)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-2-hydroxymethyl-phenyl)-8-fluoro-2H-phthalazin-1-one;2-{3-[5-(5-Azetidin-1-ylmethyl-pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl]-2-hydroxymethyl-phenyl}-6-tert-butyl-8-fluoro-2H-phthalazin-1-one;6-tert-Butyl-2-{3-[5-(5-dimethylaminomethyl-pyridin-2-ylamino)-1-methy-1-6-oxo-1,6-dihydro-pyridazin-3-yl]-2-hydroxymethyl-phenyl}-8-fluoro-2H-phthalazin-1-one;6-tert-Butyl-2-(3-{5-[(1R,5S)-5-(3,8-diaza-bicyclo[3.2.1]oct-8-yl)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-2-hydroxymethyl-phenyl)-8-fluoro-2H-phthalazin-1-one;6-{6-[3-(6-tert-Butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-2-methyl-3-oxo-2,3-dihydro-pyridazin-4-ylamino}-N,N-dimethyl-nicotinamide;6-tert-Butyl-8-fluoro-2-{2-hydroxymethyl-3-[1-methyl-6-oxo-5-(5-trifluoromethyl-pyrazin-2-ylamino)-1,6-dihydro-pyridazin-3-yl]-phenyl}-2H-phthalazin-1-one;6-tert-Butyl-8-fluoro-2-(3-{5-[5-(2-hydroxy-1,1-dimethyl-ethoxy)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-2-hydroxymethyl-phenyl)-2H-phthalazin-1-one;2-(3-{5-[5-(2-Azetidin-1-yl-1,1-dimethyl-ethoxy)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-2-hydroxymethyl-phenyl)-6-tert-butyl-8-fluoro-2H-phthalazin-1-one;6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{5-[5-(2-hydroxy-2-methyl-propoxy)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one;2-[8-Fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-1-oxo-1,2-dihydro-isoquinolin-6-yl]-2-methyl-propionitrile;6-tert-Butyl-8-fluoro-2-(3-{5-[5-((S)-2-hydroxy-3-methoxy-propoxy)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-2-hydroxymethyl-phenyl)-2H-phthalazin-1-one;6-tert-Butyl-8-fluoro-2-(3-{5-[5-((R)-2-hydroxy-3-methoxy-propoxy)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-2-hydroxymethyl-phenyl)-2H-phthalazin-1-one;6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-((S)-1-methyl-pyrrolidin-2-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one;6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-((R)-1-methyl-pyrrolidin-2-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one;6-{6-[3-(6-tert-Butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-2-methyl-3-oxo-2,3-dihydro-pyridazin-4-ylamino}-N,N-dimethyl-nicotinamide;6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{5-[5-(4-hydroxy-4-methyl-piperidine-1-carbonyl)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one;6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(6-methyl-2,6-diaza-spiro[3.3]hept-2-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one;6-tert-Butyl-2-{3-[5-(5-ethanesulfonyl-pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl]-2-hydroxymethyl-phenyl}-8-fluoro-2H-phthalazin-1-one;6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-6-oxo-5-[5-(propane-2-sulfonyl)-pyridin-2-ylamino]-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one;6-tert-Butyl-8-fluoro-2-(3-{5-[5-(2-hydroxy-ethylsulfanyl)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-2-hydroxymethyl-phenyl)-2H-phthalazin-1-one;6-tert-Butyl-8-fluoro-2-(3-{5-[5-(2-hydroxy-ethanesulfonyl)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-2-hydroxymethyl-phenyl)-2H-phthalazin-1-one;6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{5-[5-(4-isopropyl-piperazin-1-yl)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one;6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(1-methyl-pyrrolidin-3-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one;6-tert-Butyl-8-fluoro-2-{2-hydroxymethyl-3-[5-(1′-isopropyl-1′,2′,3′,4′,5′,6′-hexahydro-[3,4]bipyridinyl-6-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl]-phenyl}-2H-phthalazin-1-one;6-tert-Butyl-2-{3-[5-(1′-ethyl-1′,2′,3′,4′,5′,6′-hexahydro-[3,4]bipyridinyl-6-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl]-2-hydroxymethyl-phenyl}-8-fluoro-2H-phthalazin-1-one;6-tert-Butyl-2-{3-[5-(1,5-dimethyl-1H-pyrazol-3-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl]-2-hydroxymethyl-phenyl}-8-fluoro-2H-phthalazin-1-one;6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-((S)-1-methyl-pyrrolidin-3-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one;6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-((R)-1-methyl-pyrrolidin-3-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one;6-tert-Butyl-8-fluoro-2-{2-hydroxymethyl-3-[1-methyl-5-(4-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-ylamino)-6-oxo-1,6-dihydro-pyridazin-3-yl]-phenyl}-2H-phthalazin-1-one;6-tert-Butyl-2-{3-[5-(5-cyclobutylaminomethyl-pyrazin-2-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl]-2-hydroxymethyl-phenyl}-8-fluoro-2H-phthalazin-1-one;6-tert-Butyl-2-(3-{5-[5-(2-dimethylamino-ethoxy)-pyrazin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-2-hydroxymethyl-phenyl)-8-fluoro-2H-phthalazin-1-one;6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methyl-piperazin-1-ylmethyl)-pyrazin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one;6-tert-Butyl-2-(3-{5-[5-(2-dimethylamino-1,1-dimethyl-ethoxy)-pyrazin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-2-hydroxymethyl-phenyl)-8-fluoro-2H-phthalazin-1-one;6-tert-Butyl-2-(3-{5-[6-(2-dimethylamino-1,1-dimethyl-ethoxy)-pyridazin-3-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-2-hydroxymethyl-phenyl)-8-fluoro-2H-phthalazin-1-one;6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[6-(1-methyl-piperidin-4-yl)-pyridazin-3-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one;6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one;6-tert-Butyl-8-fluoro-2-[2-hydroxymethyl-3-(5-{5-[(2-methoxy-ethylamino)-methyl]-pyridin-2-ylamino}-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl)-phenyl]-2H-phthalazin-1-one;6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-((1S,4S)-5-methyl-2,5-diaza-bicyclo[2.2.1]hept-2-ylmethyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one;6-tert-Butyl-8-fluoro-2-{2-hydroxymethyl-3-[5-(5-{[(2-methoxy-ethyl)-methyl-amino]-methyl}-pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl]-phenyl}-2H-phthalazin-1-one;6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[6-(4-methyl-piperazin-1-yl)-pyridazin-3-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one;6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[6-((1S,4S)-5-methyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-pyridazin-3-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one;2-(3-{5-[5-(Azetidine-1-carbonyl)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-2-hydroxymethyl-phenyl)-6-tert-butyl-8-fluoro-2H-phthalazin-1-one;6-tert-Butyl-2-(3-{5-[5-(1,1-dioxo-1λ6-thiomorpholine-4-carbonyl)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-2-hydroxymethyl-phenyl)-8-fluoro-2H-phthalazin-1-one;6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(2-oxa-6-aza-spiro[3.3]heptane-6-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one;6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(6-methyl-2,6-diaza-spiro[3.3]heptane-2-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one;6-{6-[3-(6-tert-Butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-2-methyl-3-oxo-2,3-dihydro-pyridazin-4-ylamino}-N-(2-dimethylamino-ethyl)-nicotinamide;6-{6-[3-(6-tert-Butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-2-methyl-3-oxo-2,3-dihydro-pyridazin-4-ylamino}-N-(2-hydroxy-ethyl)-N-methyl-nicotinamide;1-(6-{6-[3-(6-tert-Butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-2-methyl-3-oxo-2,3-dihydro-pyridazin-4-ylamino}-pyridine-3-carbonyl)-azetidine-3-carbonitrile;6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{5-[5-(3-hydroxy-pyrrolidine-1-carbonyl)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one;6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{5-[5-(4-hydroxy-piperidine-1-carbonyl)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one;6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methyl-piperazin-1-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one;6-tert-Butyl-2-(3-{5-[5-((S)-1,2-dihydroxy-ethyl)-pyrazin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-2-hydroxymethyl-phenyl)-8-fluoro-2H-phthalazin-1-one;2-{3-[5-(5-Azetidin-1-ylmethyl-1-methyl-1H-pyrazol-3-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl]-2-hydroxymethyl-phenyl}-6-tert-butyl-8-fluoro-2H-phthalazin-1-one;6-tert-Butyl-8-fluoro-2-{2-hydroxymethyl-3-[1-methyl-5-(5-methyl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazin-2-ylamino)-6-oxo-1,6-dihydro-pyridazin-3-yl]-phenyl}-2H-phthalazin-1-one;6-tert-Butyl-8-fluoro-2-{2-hydroxymethyl-3-[1-methyl-5-(5-oxetan-3-yl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazin-2-ylamino)-6-oxo-1,6-dihydro-pyridazin-3-yl]-phenyl}-2H-phthalazin-1-one;6-tert-Butyl-8-fluoro-2-{3-[5-(1′,2′,3′,4′,5′,6′-hexahydro-[3,4]bipyridinyl-6-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl]-2-hydroxymethyl-phenyl}-2H-phthalazin-1-one;6-tert-Butyl-8-fluoro-2-{2-hydroxymethyl-3-[5-(1′-methanesulfonyl-1′,2′,3′,4′,5′,6′-hexahydro-[3,4]bipyridinyl-6-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl]-phenyl}-2H-phthalazin-1-one;2-{3-[5-(1′-Acetyl-1′,2′,3′,4′,5′,6′-hexahydro-[3,4]bipyridinyl-6-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl]-2-hydroxymethyl-phenyl}-6-tert-butyl-8-fluoro-2H-phthalazin-1-one;6-tert-Butyl-8-fluoro-2-{2-hydroxymethyl-3-[5-(4-hydroxy-4-methyl-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl]-phenyl}-2H-phthalazin-1-one;6-tert-Butyl-8-fluoro-2-{2-hydroxymethyl-3-[5-(4-hydroxy-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl]-phenyl}-2H-phthalazin-1-one;6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-((1R,5S)-3-methyl-3,8-diaza-bicyclo[3.2.1]oct-8-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one;6-tert-Butyl-8-fluoro-2-{2-hydroxymethyl-3-[1-methyl-5-(1′-methyl-1′,2′,3′,4′,5′,6′-hexahydro-[3,4]bipyridinyl-6-ylamino)-6-oxo-1,6-dihydro-pyridazin-3-yl]-phenyl}-2H-phthalazin-1-one;6-tert-Butyl-2-(3-{5-[1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-2-hydroxymethyl-phenyl)-8-fluoro-2H-phthalazin-1-one;6-tert-Butyl-2-(3-{5-[5-(4-ethyl-piperazin-1-yl)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-2-hydroxymethyl-phenyl)-8-fluoro-2H-phthalazin-1-one;6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{5-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one;2-(8-Fluoro-2-{2-hydroxymethyl-3-[1-methyl-5-(1′-methyl-1′,2′,3′,4′,5′,6′-hexahydro-[3,4]bipyridinyl-6-ylamino)-6-oxo-1,6-dihydro-pyridazin-3-yl]-phenyl}-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-methyl-propionitrile;2-(2-{3-[5-(5-Azetidin-1-ylmethyl-1-methyl-1H-pyrazol-3-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl]-2-hydroxymethyl-phenyl}-8-fluoro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-methyl-propionitrile;2-[2-(3-{5-[5-(2-Azetidin-1-yl-1,1-dimethyl-ethoxy)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-2-hydroxymethyl-phenyl)-8-fluoro-1-oxo-1,2-dihydro-isoquinolin-6-yl]-2-methyl-propionitrile;2-(8-Fluoro-2-{2-hydroxymethyl-3-[1-methyl-5-(5-methyl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazin-2-ylamino)-6-oxo-1,6-dihydro-pyridazin-3-yl]-phenyl}-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-methyl-propionitrile;6-(6-{3-[6-(Cyano-dimethyl-methyl)-8-fluoro-1-oxo-1H-isoquinolin-2-yl]-2-hydroxymethyl-phenyl}-2-methyl-3-oxo-2,3-dihydro-pyridazin-4-ylamino)-N,N-dimethyl-nicotinamide;2-[8-Fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-((S)-1-methyl-pyrrolidin-2-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-1-oxo-1,2-dihydro-isoquinolin-6-yl]-2-methyl-propionitrile;2-[8-Fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-((S)-1-methyl-pyrrolidin-3-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-1-oxo-1,2-dihydro-isoquinolin-6-yl]-2-methyl-propionitrile;2-[2-(3-{5-[5-(2-Azetidin-1-yl-1,1-dimethyl-ethoxy)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-2-hydroxymethyl-phenyl)-8-fluoro-1-oxo-1,2,3,4-tetrahydro-isoquinolin-6-yl]-2-methyl-propionitrile;2-(8-Fluoro-2-{2-hydroxymethyl-3-[1-methyl-5-(5-oxetan-3-yl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazin-2-ylamino)-6-oxo-1,6-dihydro-pyridazin-3-yl]-phenyl}-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-methyl-propionitrile;6-tert-Butyl-8-fluoro-2-{2-hydroxymethyl-3-[1-methyl-5-(1′-oxetan-3-yl-1′,2′,3′,4′,5′,6′-hexahydro-[3,4]bipyridinyl-6-ylamino)-6-oxo-1,6-dihydro-pyridazin-3-yl]-phenyl}-2H-phthalazin-1-one;2-(8-Fluoro-2-{2-hydroxymethyl-3-[1-methyl-5-(1′-oxetan-3-yl-1′,2′,3′,4′,5′,6′-hexahydro-[3,4]bipyridinyl-6-ylamino)-6-oxo-1,6-dihydro-pyridazin-3-yl]-phenyl}-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-methyl-propionitrile;6-tert-Butyl-2-{3-[5-(5-ethyl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazin-2-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl]-2-hydroxymethyl-phenyl}-8-fluoro-2H-phthalazin-1-one;2-(2-{3-[5-(5-Ethyl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazin-2-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl]-2-hydroxymethyl-phenyl}-8-fluoro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-methyl-propionitrile;6-tert-Butyl-2-[3-(5-{5-[(1S,4S)-1-(2,5-diaza-bicyclo[2.2.1]hept-2-yl)methyl]-pyridin-2-ylamino}-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl)-2-hydroxymethyl-phenyl]-8-fluoro-2H-phthalazin-1-one;6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{5-[5-(4-hydroxy-4-methyl-piperidin-1-ylmethyl)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one;4-(6-{6-[3-(6-tert-Butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-2-methyl-3-oxo-2,3-dihydro-pyridazin-4-ylamino}-pyridin-3-yl)-piperazine-1-carboxylicacid ethyl ester;8-Fluoro-6-(2-fluoro-1,1-dimethyl-ethyl)-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-isoquinolin-1-one;6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-((1S,4S)-5-methyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-pyrazin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one;2-[8-Fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-((R)-1-methyl-pyrrolidin-3-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-1-oxo-1,2-dihydro-isoquinolin-6-yl]-2-methyl-propionitrile;and6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-6-oxo-5-[1′-(2,2,2-trifluoro-ethyl)-1′,2′,3′,4′,5′,6′-hexahydro-[3,4]bipyridinyl-6-ylamino]-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one.16. A method for treating an inflammatory and/or autoimmune conditioncomprising administering to a patient in need thereof a therapeuticallyeffective amount of the compound of claim
 1. 17. A method for treatingrheumatoid arthritis comprising administering to a patient in needthereof a therapeutically effective amount of the compound of claim 1.18. A method for treating asthma comprising administering to a patientin need thereof a therapeutically effective amount of the compound ofclaim
 1. 19. A pharmaceutical composition comprising the compound ofclaim
 1. 20. A pharmaceutical composition comprising the compound ofclaim 1, admixed with at least one pharmaceutically acceptable carrier,excipient or diluent.